TW202448B - - Google Patents

Abstract

These compounds correspond to the formula: <IMAGE> in which R1 represents H or an alkyl, phenylalkyl, aminoalkyl, optionally esterified carboxyalkyl, cyanoalkyl, carbamoylalkyl, hydroxyalkyl or alkoxyalkyl group; RIV represents an optionally substituted cycloalkyl group or an aromatic group such as an optionally substituted phenyl or heterocycle or RIV and RV together represent the group: <IMAGE> in which u has the value 1 to 3, optionally carrying (np) substituents Xp chosen from halogen, alkyl, alkoxy, nitro and trifluoromethyl, and np have a value from 0 to 3; RV represents a group (CH2)m-X in which m is 0 to 5 and X represents a halogen, a cycloalkyl, an optionally substituted phenyl, a group COOX1; -O-COX1; -SCOX1; (O)q-S-X1 with q = 0, 1 or 2; -O-COOX1; -N-X3-CO-X1 with X3 = H or alkyl; <IMAGE> with W = O or S and X1 being a C1 to C3 alkyl or an optionally substituted phenyl; a group -COX1X2; -O-CO-NX1X2; or -NX1X2; in which X1 represents an alkyl or phenyl which can be substituted, an alkoxy, or an optionally substituted cyclic or linear amine; a hydroxyl or carboxylic acid group; and Z represents a heterocycle containing one or more heteroatoms chosen from O, S and N, condensed with an aromatic ring which can also contain a heteroatom and which can be substituted, as well as their addition salts.

Description

£ 02448 Λ 6 ___ Π_6_ V. Description of the invention (1) The present invention is a heterocyclic derivative subjected to interaction with cholecystokinin and gastrin. The visceral saccharin (CCK) is a peptide hormone which occurs in several forms containing 8-39 amino acids in the body. It holds many physiological activities on the bile duct, the intestinal tract, and on the mid-lime and the peripheral nervous system. Refer to the paper by JE Morley in Life Sciences, 1982, 3Q. P. 479-493, this article represents its own nature Jia Yi's detailed review. By specific antagonism, two different groups of CCK and β have been detected; the type A group "especially the pancreas • the sac and certain areas of the central nervous system • type B mainly occurs in the central nerve system. May secretin is a peptide called chlormonimum, which has a particular effect on the acidic compartment of may: its 5C-amino acid is the same as CCI (the same. The secretin and / or CCK-antagonist compounds have been described by fans, especially It is progluBide, p-gas benzol-L-tryptophan, or the most recent substituted benzodiazepine leather. It is a specific antagonist of CCK A by "Such as 3S (-)-N-2- n-methyl-2-oxy-5-phenyl-2,3-dihydrobenzocyano-3-yl] -2-indolecarboxamide (J. Med. Che · .. 1988 · 3 丄, 2235-46) or CCK B is antagonized by the specificity of Yang · such as 3R (ONU-methyl-2-oxy-5-phenyl-2,3-diβ-1Η-1,4- Benbendi "Yuange-3-yl] -Η ·-[3-tolyl] _ (£» 1 "." Pharmacology, 1989, L £ L2_, 273-280) 0 Cuzazole CCK-antagonist was Described in the soft state patent-A-0432 040. |, | II &quot; ....................................... ..________. Moreover, the substituted thiazole of the following formula (A): (Please read the complaint first and ^ Notes ^ Freak to write this page) -3-This paper is used for 8 countries in the standard size ¥: SAMPLE (CMS) Specifications (210x297 g) 81. 6. 10,000 sheets (H) 202448 Λ 6 η 6 V. Description of the invention (2) Η

A

NHCO (A) where At stands for 2,4-dimethoxybenzyl; 2,3,4-trimethoxybenzyl or cockroach ring groups, such as 3,4-dihydride-7-methoxy-2,2 , 8-trimethylbenzopyridin-1-211-6-yl or 3,4-dihydride-7-methoxy-2,2-dimethylbenzopyridin-1-yl-2 H -6-base, described in Indian J. C he., S ec. B. 1988, 27 (B) 7, 629-32, as a bactericidal or bactericidal fungi

NHC

B (B) (Please read the notes on the back of Erguo to write this page first) 装-线-The Ministry of Economics 楮 楊 汀 戀 An An industrial and consumer cooperation cooperative Indian slave squadron representative 氲 or Australian atom person is described in Che. . Pha "i 1977, 25 (9), 2292-9 · As an anti-inflammatory eye-catcher. Other substituted oxazoles of formula Ο: ** 1 -....... ho2ch2c ^ s ^ nhco- &lt; ^ 〇)

• N C〇2H

Bull

Cl

(Q This paper is used for the standard side a B home standard (CNS) TM regulations Dai (210> &lt; 297 public: «:) 81. 6, 10,000 sheets (H) 202448 Λ 6 Π 6 V. Invention description (5 ) Possess immuno-enhancing and anti-inflammatory encyclopedia and is described in Arch. Ieiunol. Ther. Exp., 1978, 26 (1-6), 921-9〇, the formula 4-substituted 4-carbocarboxylamine: Η

NHCO

(D) It is mentioned in Che ·. Abst. 112 (13), 115589 x and is regarded as possessing bacillus-killing and poisoning properties. The compound according to the invention is a suspected «substituted 2-aminothiazole of formula (I)

R V,

Rl I N-C-Z II 〇 (Please read the precautions before filling in this page) Install & Order _ Line_

R

N (I)

IV The Ministry of Economy ’s Standards Advise Π 工 消 &quot; Cooperatives to print the formula-Ri stands for fi atom; (Ci- ") alkyl or benzene alkylene group with (Ci-C *) alkyl; formula-Zi-NI ^ IU Aminoalkylene group • where h represents (C2-C4) nicotine group and R * and Re represent Η or (“-Cd alkyl or 5- and this paper scale is used in the S Η family standard ( CNS) Ή specification (210X29V male dragon) 81. 6. 10,000 sheets (Η) Λ 6 Π6 V. Description of the invention ⑷ gjg is connected to "atoms, forming 鰌 and _ 瓖 such as: 嚅« base,% pyrrolidyl, H- Hexa «pyridinyl, hexahydropyridinyl or (Ci-Cs) 4-alkylhexahydropyridinium ;; S-Z2COORe optionally esterifies the carboxynicotinoyl group • where Z2 represents (Cl-c *) And R «represents η or ((Μβ) alkyl; (c2-ce> mg think 3i; the formula -Za-COHR ^ Re amine methyl nicotinic group • where Z3 represents (Ci-Cd sub h and R * represent Η or (Ci- “) alkyl, or 盧 瓖 with Η for example: NR * RS; (Cz-Ce) hydroxyidene II, or ih-Cio) alkoxyalkylene; _ RIV Represents unsubstituted or substituted with one or more strontium (Ci-D alkyl (C3-C7) cycloalkyl; aryl such as phenyl which is unsubstituted or strontium one or Phenol selected from halogen * especially gas or fluorine substituents, (Ci-Ce) alkyl * and (Ci-Cs) alkoxy and thioalkoxy, nitro and trifluoromethyl or such as trioxa Contains at least one heteroatom selected from 〇, s and Η, especially fur_-yl, thienyl, pyrrolyl, pyrazolyl · imidazolyl, pyridyl • pyroctyl, "1« group and thiazolyl. It is subject to (Ct-Cs) alkyl or di-so atom or (Ci-Ca) alkoxy substituted for Riv and Rv ......................... ---------,

Economic Lang Langyang asked half to persuade A Gongxiao to cooperate Du Yin 51 «Taste only the 4th position of the stupid carbon combination and where u is equal to 1-3, depending on the situation with one or more sessions Up) substituent U, which For phases or phases, m is from a halogen atom, (G-Cd alkyl and alkoxy, and the base and trifluoromethyl · -6- 81. 6. 10, 〇〇〇 Zhang (Η) (please First read the back and the notes # 蜞 write this page) This paper is 5 people-scale side-by-side Zhongming Η family standard (CNS) TM regulations (210X297 degrees) 202448 82.12.2 2 Λ 6 [? 6 V. Description of invention ( 5) np is equal to 0-3; '-Rv represents-(CH2) _-X group, where β is 0-5 and X represents •' halogen atom • preferably bromine atom, hydroxyl · (C3-C7) cycloalkyl , Phenyl which may be selected from a halogen atom · (Ca-Cs) alkyl or alkoxy ', or nitro, amine * hydroxy or trifluoromethyl one of which is substituted by -COOH; -COOXj- O-COX !; -SCOX !; (OJq-S-Xi with.q = 0.1 or 2; -O-COOXj; N-CO-Xi with X3 = H or (C ^ Cj) .alkyl; X3 -NH- COX ,; -OC-NH-Xi; -NH-C-NHXi with W = O or S; II «I〇〇w -NH ~ C- (CH2) b-C00H with s = 2,3,4II o ( Please read the notes of πώ '# Difficulty Page) Binding-Ordered by the Ministry of Economic Affairs to be compliant and printed by the Cooperative Society 5i which represents (Ci-Ce) alkyl; phenyl which can be selected from halogen atoms for one or more sessions ("-(: 3) Alkyl or alkoxy or nitro, amino • hydroxy or trifluoromethyl substituted; adamantyl; selected from one of -CONXiXz; -NXiXa; wherein Xi represents hydrogen · (C / Ca) alkyl or The stupid group is unsubstituted or buried for one or more times from the halogen atom '· (Ci-U burning or alkoxy or nitro, amine or trifluoromethyl substituted and 5U represents a hydrogen atom, (Ca -Ca) alkyl &lt; or change to ¥ 1 and 5 &lt; 2 and the nitrogen atom to which it is connected constitutes a heterocyclic ring. This heterocyclic ring is derived from pyrrolidine or hexafi pyridine, which is unsubstituted or substituted by hydroxy or hydroxy In the latter case, the latter is unsubstituted or substituted by 豳 group or substituted by -cooXise-conXiXz group; -7- This standard method is used in the middle of the standard Η H 1MCNS) ΊΜ 簂 (210x297 公 犮) 81. 6. 10,000¾ (Η) line. The Ministry of Economy ’s quasi-square and Π Gong Xiao Yang cooperation Du Yin 5i £ 02448 Λ 6 ___ Π_6_ V. Description of the invention (6) or change to Rvaa-C »*) alkoxy; hydroxyl; 5 or 6 yuan is not substituted or oxygen Or hydroxy-substituted cyclic amine; unsubstituted or substituted -COOAlk N-substituted hexahydropyridyl • where Aik represents (Ci-CB) alkyl; carboxylate · -ΝΧ2Χ «group, X« = H or X4 =-(CH2) t: -Xe, t is equal to 2, 3 or 4 and IU stands for -0H, -O-CO-Rz · -HHCORz · -HH-C-HHR2

(I Ο where represents (Ci-Ce) alkyl; or -HR2R3 group • where | ^ 2 or Rs respectively represents H * (Ci-Ce) alkyl, unsubstituted or substituted by one or more e substituents benzene The substituent is selected from a halogen atom or a (Ci-Ca) alkyl group or (Ci-Ca) alkoxy group • or R 2 and R 3 and the nitrogen atom to which they are connected constitute a 5 or 6-membered ring;- Z represents a heterogen containing one or more heteroatoms selected from 0, S and N heteroatoms, coupled to an aromatic ring * It may contain a copious atom selected from 0, S and N and may be substituted by one or more groups , This substituent is from a halogen atom. (H-Cs) Alkyl and alkoxy, or benzyl group • nitro, amine and trifluoromethyl · "I atom Η may be aromatic or in -NH form , Which is unsubstituted or substituted by ("-C *) alkyl, carboxyalkylene-24-(: 00111〇 • wherein Z4 represents (Ci-") alkylene and is H * benzyl or (Ci-Ce ) Alkyl; aminomethyl-alkylene-Ze-CONRuR ^, where Re represents (“-C *) alkylene and Ru and 1-12 represent η, (C ^ -Ce) alkyl • or with Ν Saturated heterocycle such as morpholinyl or hexahydropyridyl; Bf * COR13, R13 represents (C ^ U) alkyl or stupyl; alkoxy stage -C00R14, R14 is the third-butyl * or benzyl; -8 _ This paper size is easy to use Zhongqu Η home-like 1HCNS) 1M specifications (210X297 male dragon) 81. 6, 10 000 sheets (H) (please read first # 背 而 &lt; Precautions will be written on this page) _ _ binding · thread. 203448 Λ 6 Π 6 V. Description of the invention (7) and the additional reels of these compounds and organic acids or organic acids and sickles; the invention also includes Preparation of the B-th acceptable non-toxic salts, but other compounds that can be used to isolate or purify the compound of formula (I) are also included in the present invention alkyl, alkylene, alkoxy and alkoxy alkoxy The base may be suspected or branched, °, / Z especially represents benzo_phenyl, benzofuryl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, indolyl, Isoindolyl • Indolinyl · «Isoindolinyl, nozinolyl, iso-pyridinyl, branched cinnolinyl, oxazolinyl, beerlinyl and [2,3-c] -thieno Or [3,2-c] pyridyl. When Z represents an indolyl group of the following formula: (Please read # 背 而 之 _Cautions before filling out this page) Binding · / (Xi) ni

Line R 9-Ministry of Economic Affairs Standards (0 卩 工 消 价 合作社 印? 4 In the formula (Xdu stands for aromatic ring depending on the situation, the substituent * Re may represent H; (UC *) alkyl; formula- Z-C00Rlo is based on the fact that the carboxyalkylene group is substituted, where Z * represents a (Ci- ") subunit and R10 represents H · benzyl or (" -Ce) alkyl; an amine of the formula -Ze-CONR ^ Ru Carboxyalkylene, where Rn and R12 represent Η or (C ^ -Ce) alkyl or form a planicyclic and heterocyclic ring with N. This heterocyclic ring is selected from the group consisting of porphyrinyl or hexapyridyl and alkylene: the formula COR13 Brewing Qi * where R13 stands for (Ci-C *) alkyl or phenyl •• type paper 5JL scale for SB family details (CNS) &quot; ΡΊ specification (210x297 male dragon) 81. 6. 10,000 sheets (H ) 202448 Λ 6 Π 6 V. Description of the invention (8) C00R14 alkoxycarbonyl group • which represents the third butyl or benzyl group. I &gt; Of the compounds of formula (I), IU represents hydrogen is more preferred and more particular The ground is those where Z represents a «dolyl group which is substituted or unsubstituted on the krypton atom; a phenyl group is preferred in the RIV group. The subject of the present invention is also the preparation of compounds of formula (I), which is obtained by the formula (I ) Of:

(Please read first, · ** ,? 背 而 · v / Notices #Dang write this page) The Ministry of Economic Affairs has approved the central government and set up a cooperative cooperative to print 5i in the iU · RIV and "have (I) 's established Meaning, under the general conditions of amine brewing * and acid of the formula Z'COOH • where Z 'represents Z or a substituted Z, where the reactive group of Z has been protected by sulfonium, and fU, Rv, RIV and Z The same meaning as in formula (I) · or the activated form of the acid Z'COOH, such as sugar halide • anhydride • preferably mixed anhydride such as carbonic anhydride, or activated ester reaction • to obtain a trial for common use in peptide synthesis Compound (Π) can be protected; in this case, it represents the same substituted amine, the existing amine group is protected, RIVA and RVA represent the same substituents as RIV and Rv • where the hydroxyl or amine group is 0- and N- 保 罐 0-Once this base is protected, if it is required • after the Puhe • can be subjected to an immediate deprotection reaction. Many aminothiazoles of formula (I) are known compounds., -10- The 5fc scale of this paper is used in the "B Family" (CNS) tM specification (2 丨 0x297 public) 81. 6. 10,000 sheets (H) 2,02448 Λ 6 Π 6 5. Description of the invention (9) This new amine Hipzole can be prepared according to one of the methods described in Bull. Soc. Chia (c &gt; 1963, 2498-2503. In general, the sham is pseudo-α-formed according to the following reaction scheme, preferably bromoketone reaction: m η丄 NHR,

Rvv / Br

R

NH 十 2 ^ ιν ο

丨,-Dirty: One N (please read ^ 'on the contrary, note #fill in this tile)

R

IV m

IV π

Ri, RIV and Rv have the same meaning as those of formula U). A variety of different compounds (made by those who represent amine alkyl groups in JJ "Described in the Ministry of Economic Affairs, Ministry of Economic Affairs and the People's Republic of China = 5 Gong Xiaotong Cooperative Society Printed 5i European Patent-A-0,283,390 ◊ ____________________ ·-· ------ ------- ------,....... ~ C (-halogenated ketones and thioureas can be prepared by methods described in the literature on their principles; therefore, ct- Brominated ketone (IV) can be prepared by reacting with RvCHaCORzv and bromine; reacting in an acid base or with brominated bromide in an organic solvent such as ethyl acetate • containing "solvent or its mixed solution". Shi Aromatics _ are generally prepared by the Friede Bu Crafts reaction, while the Cell Methyl _ can be prepared by the hydrolysis of the corresponding diazo ketone by diazomethane and "when the carboxylic acid gas reacts * _ α-Aromatic Aromatic Aromatics Ketones can be borrowed from Friedel-Crafts reaction, using DiDang α-11 paper scales and using Zhongming a's standard (CNS) Τ4 specifications (2U1X29 Yageong) 81. 6.】 〇, 000 sheets (H) 202448 A 6 η 6 V. The invention d (10) Prepared by acetyl chloride. When Rv represents a sugar group ((: 112:) _- (: 0 (^ 1, the corresponding substituted thiazole of the following formula (V) RIV, / 1 and as defined by (I) • or known compounds, prepared according to known methods α- or α- bromoacetyl stuffed bromo keto acid ester with urea according to the following reaction scheme Dui reaction of:., '' Li 2 flooded

Br 2 RIV-C〇 '-(CH2) m + rCOOX!' ~ ► Riy-CO-CH- (CH2) m-COOX!

Br (please read -ift's note and notes before writing this page)

= S H〆

X NHCOZ ♦ Saccharification and backwashing

X1〇C- (CH2)] o R

Ύ -N

NH 2

IV (la) (V) The Ministry of Economic Affairs is approved by the central government, and the price is printed by the cooperative. According to the value obtained: base Rv, the following preparation method is used: a)-When Rv stands for -_ (CH2) «-0H base At the time, the corresponding substituted 2-amino-oxazoles of the following formula (VI), where as defined in (I), can be derived from the above ester (V), depending on the use of gold hydride for example: lithium aluminum hydride A medicinal agent such as tetrahydrofuran buried in the original formula (VI) amino enzyme: H〇- (CH2) m ^ S 丫 NH:

• N

R

IV (VI) -12 This paper is used in "Qu Qu 1 Ϊ Apple (CNS) IM regulation t5 (2K) x297 male dragon) 81. 6. 10,000¾ (H) 202448 Λ 6 Π 6 V. Description of invention ( 11) (VI) Using ZC00H to obtain the compound of formula (I b) HO- (CH2),

τ -N

NHCOZ

R

IV (lb) where ·, RIV and Z are as defined in (I); b) when Rv stands for 鈮 基-(CHaVM-O-CO-Xi or indeed _ where iXiRq is as defined in (I), 纆Substitute 2-amino-oxazole (tune) * (Vic) or (VId) where Riv * ς, "ϊ, W and XiWU) can be prepared according to the following method_ according to the following procedure 3: (Please read first -For further considerations, please fill in this page.) The Ministry of Economic Affairs, Jiyang, quasi-work consumption &quot; Cooperative cooperative seal 14 -13, the standard is used in the "81 family quasi (€ 肊) 〒 &lt; 1 regulations Dai (210 father 297 male dragon) 81. 6. 10,000 sheets (H) 202448 .., 12. Fifth, the invention of Hu (12)

Nal RIV &quot; Jy'lCH2) m + l'Cl Ο CH ^ COCH ^

Riw-C-iCHT) -1V li-m + 1 O X ^ H R: IV-CO-CH- (CH2) m-W-CO-X1

0 4 Γ5ΧΙ 6 〇 Q i X, C〇WwκΓ or X ^ OW Cs, (please read ^ Backward Note ‘Notes before writing this page)

Br (W = O or S)

H ^ N

C ΗλΝ II 〇

Rt S, / NH2 醢 化 反 ® N -► (Ic) 〇r (Id) X, -C-W. (CH2) m.

(vnc) or (VHd) The Ministry of Economic Affairs of the People's Republic of China quasi-A Agong ·· \ ·· Cooperative Du Yin 31 R.

YY nh2 s

II nh-,-c-nh2 N ^ ~:-R ^ -C-CH-CC ^ J ^ -SX,

-14- The size of this paper is generally applicable to the IM standard of the Ming Dynasty (CNS) (210x2974 *) ία 6 • Br- 81. 6. 10,000 sheets (Η) £ 02448 Λ 6η 6 V. Invention 4 (13)- Or by Ν-protected leaven (VI) as defined above 'reaction with glycosyl hydrogen such as ethyl monoxide v in a solvent such as ϋ, to obtain an ester of the formula:

Xi-C-〇- (CH2) i YSY • N ΜΗ ·

R

IV (Vllc) with W = 0 or

-XrC-0- (CH2) ^ NHCOZ

R

N (please read-; '*? Back to the side of the note to write this page) IV, (Ic) where Xi * ·, RIV or Z are as defined in (I) above; c) -When Rv Represents aminocarbamate-(CHzh-O-CO-HHXi, where ϋ and Q1 are as defined in (I), the substituted thiazole according to the present invention is composed of the corresponding hydroxylated compound (I b), represented by the formula Xi_N = The isocyanate with C = 0, in a solvent that is inert to the beaker, for example: tetrahydrofuran or methane gas, at 2〇Ci〇〇t: the degree of purity with the reaction, the compound of the following formula (.1 f): · Order _ The Ministry of Economic Affairs, the central government, is accurate: ^ 工 工 炸 炸 合作社 印 忆 Χι- Η

NH-COZ and Z as defined by (I); 15-Private paper size in use "W Zhu Yubi (CNS) specifications (210x297 public)

Of) 81. 6. 10,000 sheets (H) £ 02448 6: Λ6β V. Description of the invention (h) &lt; 1) Erdang {^ representative _ propanamine-((: 1 {2) * «-00. (^ : 112, where, .., .-) ^ and Xss $ D (I) are defined; 'Fu according to this issue-Mingzhi Beer makes the public opinion (乂> or _ (13) lack of corresponding _ . + Prepared in the presence or absence of solvents such as fermented yeast. Below,-. ·--It is prepared at a temperature between 2〇-12〇1; this reaction (depending on whether it is volatile) · can also be carefully sealed Carried out in the process, to get the following chemical formula (phase). Or (I g) ::, .....--, ..,....... Λ * — · ..). X : V-.,.: '.' XlX2- ^ t (CH2) ς ΝΗ,-0 YV '· Ν mr and t- matters m%

R

IV (VIII) or

XlX2-Nf (CH2) m, NHCOZο \

Ν

R

IV (Ig) The Ministry of Economic Affairs has approved it and H Gongxiao 1V. Cooperative Society Seal 31 where Χα, χ2,, RIV and, as the case may be, as defined by (I); e &gt;-when Rv represents an amine group- ( CH2) «-ΝΧ ^ Χζ, the preparation of substituted thiazoles according to the present invention is provided, for example, from the above-mentioned compound amine of formula (VI), with a gold arsenide such as lithium aluminum hydroxide, dissolved in BI such as: tetrahydrofuran * Before 201: and the melting temperature of the dissolving agent "The original compound of formula (IX):

XlX2-N- (CH2) m +;

Η- Ν

R

IV (DC) -16 The ft scale of this paper is used in the National B National Standard (CNS) 1M standard (210x297 g) 81. 6. 10,000¾ (H) 202448 Λ 6 Π 6 V. Invention two (15) ( IX} Brewed with ZC001T • Compound of formula U lh) ': X2X2-N- (CH2) m + K ς .NH-CO-Z Υ —Ν

R

IV (Ih) _ .-- · ~ ·; · r-'--' ·-·, ·, and ζ 'as defined by (I) τ: where Xi, χ2, · R: f)-i Rv Represents carbonic acid ^ ku (CH2) / -Ο-ΟΟΟΧ: ;; ::: and (.1) as defined, according to the present invention, the thio 7 saliva is made by leaven (I b) * 3 get · _ by leaven (Ib) reacted with chloroformate (nc-oxx, in the presence of cyanide such as triethylamine or pyridine) to give a compound of the formula (I u: χΊο- | -ο- (αΗ2) 〇

Υ

NH-CO-Z first read ff ιΓΓ; -¾ Matters-Item then A% ΫΊ, this page. Thread

R Ν IV. (Ii) where Xi and Z are as defined by (I), the Ministry of Economic Affairs, Jiyang Zhenzhun :; Γβ 工 消 坨 cooperative cooperative seal ¾. S)-when RIV and Rv together represent the following base: (Xp ) np. -17- This "• Zhang Scale Edge Use Zhongming® Jiabiaohua (0Ν5) ΤΊ specification (210x297 public) 81. 6.) 〇, _ 张 ⑻ £ 02448 V. Description of the invention (16) where (X »&gt;) nP and u are as defined in (I &gt;, when they are bonded via the phenyl carbon atom at the 4-position of the _azole ring; for example: in the middle of the following formula Μ 4- 奥 -211- 二 氲- 3,4- [1] -Benweiweige-5-Liang:

It was prepared according to the method described in G. Fontaine et al., CR Acad. Sci., 1965 45 83; 2-limb- 4,5-[5,4-d] -thiabo [1 ] -Benzo xepine: NH2 hydrogen (please read the notes on the back # Cao write this page)

(X) is cyclized with sulfur gland according to the general method described above, and then saccharified into a compound of the formula:

(【J) Threading-where z is as specified in (I); -18 This sheet is used in the mid-2009 National Suihan (CNS) IM specification (210X297 g) 81. 6 · 10,000 sheets (H) ^ 02448 Λ 6 Π 6 V. Description of invention Ο7) h &gt;-when Rv represents an amine group-ΗΧ2Χ4 · where Χ2 and X * are as defined by (I &gt; as defined * substituted thiwa according to the present invention · can be represented by the formula (XI &gt; The 2-amino-5-bromopazole prepared:

This compound was prepared according to J. Che ·. Soc., 1947, 1 14, and then: -Synthesis • For example: with substituted ZC00H, brewed in the presence of Β0Ρ and _ for example: triethylamine, and then The brominated derivative of formula (I k) obtained

Br, 丨 1 Υ

NH-COZ (Please read the back-to-back precautions before writing this page) Binding · Order_

R • Ν

IV (Ik) where RIV and Z are as defined by (I) • in chain leaven • at a temperature between 20Ό-melting blaze boiling temperature, replaced by amine HNX2X4 • the compound of formula (I 1) is obtained: line-economy The Ministry of Finance and Industry and A Gongxiao · ι ··· Cooperative Duyin ¾. Where X: ΧΛ-Ν 、 ^ γΝΗ-0: ΟΧ—Ν-R. (Π) and ZO as defined by (I) -19 Original paper 51 · Standard as if standard (CNS) T4 gauge Dai (210x297 public) 81. 6. 10,000¾ (H) ^ 02448 Λ 6 Π 6 V. Description of the invention (1¾-or amine HHX2X4 Substitute, then 41 will brew the 2nd position of the bite, this 2 reaction is carried out under the same conditions as the above-mentioned cypress; Π-when Rv represents-(CH2) eX group, where = 0 and X represents alkoxy, Corresponding to 2-aminothiazole is produced by 2-O-2-alkoxy-bubenylacetin, which is optionally substituted on the phenyl group. • Produces the product of formula T: ΧϊRiv

NH 2 (.ΧΓ) (please read it first, please note 亊 项 # Difficult to write this page) where RIV is as defined above and X stands for (Ci-D alkoxy, which is then compounded according to the above method, The compound of the following formula (I: Pack-

X- / S, / NH-COZ

(Im) 定 _ 线. The Ministry of Economic Affairs of the Ministry of Economics and the Ministry of Economics and Social Security 1 \-Cooperative seal 31 where Rjv and Z are as defined by (I) and X is as defined by (XI ·) · or its explicit if one of them. The compound of formula (X I ') is a new intermediate. This intermediate is also within the scope of the present invention. Some acids ZC00H or Z’COOH are well-known and even commercially available; others are made using well-known methods using similar molecules *. Therefore, the indole carboxylic acid of the following formula is hereinafter referred to as Z ”C00H:

COOH

NR (aax standard (CNS) TM standard (210X297) ¢) 81. 6. 10,000 ». (Η) 20-£ 02448 82. 12. 2? Λ 6 Η 6 V. Description of the invention (Ι 9) where Re represents alkoxycarbonylalkylene group>, which can be obtained from indole carboxylic acid, which is commercially available or obtained by conventional methods, and is prepared using the following reaction scheme 4.

COOQ COOQ ^ + R9Hal I .. Η

Ri

H 2 (X;)

COOH (please read the precautions before writing to this page) Binding. Order _ where Hal represents halogen atom and Q represents benzyl. Process ⑷ benzyl is prepared from the corresponding acid and benzyl enzyme, which are commonly used in peptide synthesis. An acid group activates cocoons in the presence of the reaction, the acid group activator such as -1, 1 · -carbonyl dipanzole , Can refer to Synthesis 1982, P. 833 · -Ν, Ν-dioxanylcarbodiimide, in the presence of 4-dimethylaminopyridine, in the next ", this can refer to J. 〇rg. Chen. 1990, 5_5_ (4), Ρ. 1390,-benzotriazolyl hexafluorophosphate (dimethylamino) period, 'this can refer to the line -21 The scale is used in the middle of a Η family quasi (CNS) T4mtM21〇x297 male dragon) 81. 6. 10,000ft (H) 202448 82, Λ 6 Β 6 V. The invention says sodium (21) where Q represents the amine Basic acid complex reaction-stress, commonly used for protecting the NH2 group, such as' COOitert-C4H9); C6Hy CH2-0-C-; CH3-C-, Ο Ο The protective group Q can be removed by the compound of the following formula:

(Please read 1 銆 關 關 關 見 話 類 丹 熚 writes this page) The Ministry of Economic Affairs's central standard 揓 Α 工 消 作 akusha cooperative seal 31 This is the winner of the method of deprotection after the conversion to the derivative (I). BOC can be radiated and pyrolyzed, and it can be removed at a temperature of 180-2001 in the absence of solvent. Indole carboxylic acid Z "C00H · Where ReSC00C (CH3) 3 or C00CH2CeHe * can be made from third butane dicarbonate_ or benzyl chloroformate® and Z" C00H · where Re = H is considered in a sickle such as triethylamine or 4-di In the presence of methylaminopyridine. In the beginning of the solvent example *: Ethylene or dichloromethane reacted to produce overseas Chinese. Acid Z ”C00H, where Rb is an alkyl group. It can be made of chlorinated chloride or acid anhydride and Z &quot; C00H * where Re = H. In the presence of triethylamine and 4-dimethylamino radicals, for example, for example: It is prepared by reaction in dichloromethane. The _-based chloride of the formula zcoci can be prepared from the mixture of soc 丨 2 or [»0 (; 13 &amp; Pa〇e and the corresponding acid *, in general, in the absence of solubles, in the reaction mixture The reaction system is prepared under the reflux a degree. Prepared. -23- This paper standard is reused in the H «Family Standard (CNS) IM specification (2 丨 0x297 male dragon) 81. 6. ιό ， 〇〇〇 Zhang (H )

202448 Λ 6 ______ Β 6 _ V. Description of the invention (22) The activation of the formula ZC00Y ”, Z’COOY” or Z ”C00Y” _, among which Y ”represents M I

The Ministry of Economic Affairs's standards and the cooperation between the work and the production of Duin 5i can consist of 1-hydroxybenzothiazole and acid, in the presence of dioxanylcarbodiimide, according to J. A ·. Che ·., Soc. 1971, 9 3 · 6318-6319 (1971) prepared by the reaction described in the method, or by hexafluoroacid 1-benzthiazolyloxy ginseng (dimethylamino) grade, according to Synthesis, 197 6, 751-7 52 The method described is prepared by reaction. The reaction of aminothiazole (H) with acid in the form of an activated ester can be carried out in a solvent. The selection of the characteristics of dissolution depends on the solubility of the compound and the type of activation of the acid group. The reaction takes place in the presence of amines such as triethylamine; this reaction is generally carried out between 0 * C-30t :. When the compound of formula (I) contains a carboxylic acid group in Z, they are prepared by preferably hydrolyzing in M-based 霣 • For example: from inorganic _t, such as the hydroxy group of sickle gold, reacted in dilute enzymes As far as the third-grade butyl ketone is obtained or prepared, it is prepared by the hydrolysis of mandelic acid. The additional η of the compound of formula (I) and the acid or Ml is prepared by introducing the acid or sickle into the solution of the compound of formula (I) in the M substitution mode. Depending on the solubility characteristics of M, after evaporation of the solution or after no solvent is added, the salt is placed in a single furnace. The compound of formula (I) and its "Class I inhibitory_cystokinin bind to its receptor. They are more or less subject to the type Α or Β is "selective • and somewhat suspected -24- this paper scale side use Chinese Η home sample standard (CNS) T4 regulation ίΜ210χ29Υ public goods) 81. 10, _ 张 （Η ) (Please read · 1-ΓΙ Contrary Precautions Λ- 塥 write this page) £ 02448 Λ 6 Π 6 V. Description of the invention (23) Divided potential may secretin antagonizes the metal. The affinity of CCK A has been determined using the method described below, and the beta is measured outside. Its principle is mentioned in Life Sciences, 1 985, ϋ (26), 2 483-2490; it includes In the slurry • The replacement of iodinated CCK 8S determined from its receptor: take a suitable pancreatic pancreatic membrane suspension (100 μg protein per minute / ml) at 1 * 1 = 7.4 out of 1 {15-11 (： 1 詒 衢 液 (50 · Μ), which contains MgCU (5 »0 * subtilisin fungus (0.1« g / liter) · Fluorinated toluene methanesulfonic acid (0.1 «g / ¾ liter) · Yu 25 t * In the presence of _ ((:! [8S (2000 Curie / milli-Ear, equivalent to 50 · Μ final concentration) and increase the degree of test substance * plug 40 minutes; this reaction borrowed Centrifuge and stop after 40 minutes. After removal of the lifting liquid • Measure the radioactivity of Nine. And at a concentration of 1 wM, in the presence of CCK 8S, quantify the non-specific combination. Under these conditions, the product of the present invention The 50% inhibitory binding concentration (ICeo) is less than 10 — M and many are about 10 μM. The economy is high: ： ： ： 工 工作 作 工作 杜 印 ¾ Its CCK B is subject to "Affinity" • Nao exists by research The replacement of iodinated CCK 8S in the homogenous receptor of Zhulian cortical homogenate was determined using the same method as CCK A. However, the suspension contains 60 micrograms of protein / ¾ litre and uses 6.5 HEPES «衢Solution (10 · Μ), which contains N3 (: 1 (130 · Μ), MgCU (5 · Μ), EDTA (1 «« M) and subtilisin H cable (250 μg / ml) and is incubated for 2 hours. At 1〇_βΜ concentration • All products are replaced by more than 25% of the CCK 8S obtained from the B receptor; some IC «〇 about 10 〇-βΜ. The most CCK B-specific compounds of the Koji receptor "Affinity is -25- 81. 6. 10, 〇〇〇 Zhang _ (phantom (please read first,? Back to t notes and then write this page) This paper scale is easy to use in the country B's last ( CNS) T4 regulation (210x297 ambassador) £ 02448 Λ 6 Η 6 V. Description of the invention fe / t) Research according to the method described below * The principle is in J. Receptor.

Res., 1983, 3_ (5), 647-655 mentioned; take turtle volume Tianzhu »thymus gland in cH = 7.4 (24.5« M) HEPES slow-balance solution, this pi® solution contains NaCl (98 · Η) · KC1 (6 · Η), NaH2P0 «(2.5bM)> Propionate (5 · Μ) ', CaCU (0.5ιΜ), MgCU (IbM), glucose (11.5 · Μ), branamine (1 · Μ) Bovine albumin (0.4 g / 100 «L), at 37 t :, in a water bath, in the presence of iodinated secretin (2-17) (2000 curies / millimol; 70 ρΗ) and Increase the concentration of the test product • Incubate for 90 minutes. The reaction was stopped by centrifugation and the radioactivity of the pill was measured; in the presence of Xiao Mi Suo (2-17), non-specific binding was determined. The ICeo value of the compound of the present invention is between 10-sM & 10-βΜ. The compounds of the present invention have also been shown to have inhibitory activity against CCK. This method is based on the "Inhibition of the Outer Mengming, Pseudo-Test FT Test Product Inhibition Effect". According to a method similar to that described in J. Biol. Che ·., 1979, 254 (12), 5321-5327, the acinar cells The CCK 8S-stimulated secretion effect of serotonin is proved • but with Tianzhu's "Secret Pancreas". The 1C 8〇 of this compound is 1〇-βΗ-1〇-βΜ. Finally, in the small white "internal test, the compound has good affinity for CCK, and antagonizes KLife Sciences, 1987, ϋ, 1631-1638 The method of description · Subcutaneous administration of CCK 8S induces the inhibitory effect of emptying; the EDBO (effective dose 50) thus obtained is "less than proglueide, a well-known secretin antagonist. If these compounds are unclear and very toxic, they can be used as the most secreted by these peptides or produced by the abnormal regulation of the biological hormonal system including them-2 6 _ 81. 6. 10,000 sheets _ (illusion to the r ii Please fill in this page again if you want to use it. This paper is for standard use. B) 戳 楳 准 (CNS) &lt; fH regulation IM2〗 0X297 public release) 202448 Λ 6 It 6 Central Ministry of Economic Affairs 惃 准 杓 Αχ; νί price cooperation Du Yinhong five 2. Description of the invention (2 彡) The treatment of physical disorders * in the intestinal area or in the central nervous system * depends on its specificity. Reference can be made to September 7-11, 1987 * JP Bali, J. Martinez article, Elsevier Science Pub. BV in &quot; Proceedings of International Synposiun on Gastrin and Cholecystokinin ’CCK and the therapeutic application of agonist antagonists Review. In particular, CCI (antagonists are useful in the treatment of leg bradykinesia such as allergic nodular syndrome, in the treatment of acute or chronic pancreatitis or the treatment of pancreatic cancer, M and appetite regulation, Or in the treatment of pain * mixed with analgesics containing opium. For more selective antagonists, they are useful in the treatment and prevention of ulcers, and in the treatment of Zollinger-Ellison syndrome. It is useful for the proliferation of G-cells or for patients suffering from esophagus, diarrhea, or lumbar cancer pain. Among A's antagonism of the degree of visceral sacral hormones • The following compounds are preferred: -2 -[Bucarboxymethyl-2- «! Indolyl) androsamino] -4-phenyl-5 acid ethyl-2-[(2-« | indolyl> minylamino] -4-phenyl 5-Phase acid ethylthiazole. Drug B according to the present invention comprises at least one compound of formula &lt; 1) or Accept one of acid or sickle salt on B. Mix with ordinary K-form agent as appropriate. Μ will constitute a B-medicine compound, which can be used in the usual way. Hydrocarbon mouth, hydrocarbon mucus • Non-hydrocarbon enteric or rectal Dosing. Dosing depends on the characteristics and severity of the disease. • Depends on the compound to be administered and the route of administration. Generally, it is used in the Cheng-27-Benjiao standard (CHS) regulation (210X297 Public and) 81 6. 10,000 Zhang (H) (please write “this page first” and then write this page) £ 02448 Λ 6 η 6 V. Description of the invention (26) Day_hang Between 20-100 ¾ grams * Injection is between 3-10 gram of the human eye and eye route. According to the invention, the drug compound is taken as tablets or granules or as a solution * suspension or It is used for parenteral administration. It is provided in the form of floating liquid or emulsion of the present invention. • In the case of oil for injection, the hydration base of the conventional side containing this type of formula is for topical administration on the skin or mucosa * In the form of creams, soft buds or percutaneous designs, they will be described in the form of suppositories and rectal capsules in the following Completion of the example to the preparation method of Chengzhong. Melt bonding, K · .P. Indicates that the nuclear magnetic resonance (NMR) spectrum is prepared for tetramethylsilane by A 2-amino substituted at the 5-position 2-amino-4- ( 2,4-Dimethoxyphenyl) -5-benzyl • Pill fl! * The hard gel form provides the sister compound to dissolve Μ or any sol. Provided according to the present invention. And some formulas I are recorded by Κ 毛 畑. Base_azole. Thiazole. For the Ming Mu capsules, the solution is available. I think it can be measured by the combination of rectal injection and IV. (Please read first, please pay attention to the jujube item Erguo write this page) Binding · Order _ Line-

(II): R, = Η; R

OCH3; Ry = -CH2 ~ \ 0 / Ministry of Economic Affairs, Central Standard ^ i; JM Industry and Consumer Cooperation Du Yin 2ί A) According to E. Thomas et al., J. Med. Chem., 1985, 2_8_, 422-446, by Friede Bu Crafts reaction, the preparation of ί 1- (2,4-dimethylaminobenzyl) -3-phenylpropane-; [-one. 28- This paper is used in the standard B) Η Family Standard (CNS) TM regulations tM2〗 〇x297 public: ¾) 81. 6. 10,000 sheets (Η) £ 02448 Λ 6 Π 6 5. Description of the invention B) According to the customary method , By using bromine in a cocoon such as dichloromethane or four-gasified carbon bromide to prepare 1- (2,4-dimethoxybenzyl) -2-bromo-3-phenylpropane-1-嗣 0 C ) 2-amino-4- (2,4-dimethoxybenzyl) -5-benzylthiazole. 4.35 grams of gland was added to 10 grams of brominated derivative prepared in 100 liters of 95 ° ethyl acetate. The reaction mixture was flowed for 3 hours. After the mixture was concentrated in vacuo, the residue was dissolved in methylene chloride, and then washed with saturated sodium carbonate (Ha2C〇3) solution. Separated by decantation, magnesium sulfate (HgSOd was dried and concentrated in vacuo. The residue was crystallized from 50 liters of dichloromethane. Weight = 7.10 g Melting point = 202-203TC: as above After preparation, the 2-aminothiazole described in the following Table 1 is prepared (please read the back of the water first and pay attention to the hardships to write this page) -29- Regulations (210x297 male dragon) 81. 6. 10,000 sheets (H) £ 02448 Λ 6 Π 6 V. Description of invention (28) Table X- (CHn) Vs.

NH-Ministry of Economics, Yan Yang, persuaded M Gong to eliminate Duan ¾ X- (CH2) m- Γ4 r'4 Luoyu; 0C OcH2 · -och3 -OCH3 119 Or -och3 -OCH3 163-164 ΛΛΗ3 -och3 -OCH3 162 A -och3 -OCH3 121 LvV / ^ X〇CH3 Λ -och3 -OCH3 176 och3 Br HH 107 -30- This paper size is used in the national S standard (CNS) IM regulations IM210X297 (commercial goods) 81. 6 . 10, 〇〇〇 Zhang (H) (please read first. Zhubei's precautions # 蜞 write this page) 装 · 线-Ministry of Economic Affairs 屮 漢 樮 切 心心 卩 工 消 &quot; Cooperative Society Seal 31 203448 Λ 6 ___ Ιί_6_ V. Description of the invention @ 9) Preparation of 2-amino group 2-amino-4-phenyl substituted by-(CIUU-COzX: or-(CH2) «-CH2〇H at the 5-position) 2-amino-4-phenyl- 5-Methoxysulfurazole (I) Ri = H; Riv = -CeHB; Rv = -CH2-C〇zCH3 Root Lo E. Knott, J. Che., Soc., 1945, 455. B) 2-amino-4-phenyl-5-hydroxyethylthiazole. 5g of the above-prepared amine base was added to a suspension containing 2g of lithium aluminum hydride and 100ml of tetrahydrofuran cooled to 0t: and the reaction mixture was refluxed for 2 hours. After cooling on an ice bath, Lu Zuan added another 2 mL of water, 1 mL of concentrated sodium hydroxide (NaOH) and 6 mL of water. • The reaction mixture was then stirred overnight. Inorganic substances are filtered and the mother liquor is concentrated under vacuum. The residue was dissolved in dichloromethane and washed with water, the land mine decanted the organic phase • placed MgS〇4 dry fiber and concentrated in public space. The residue is colored and analyzed on silica gel. * Solution * Lang: dichloromethane / middle yeast 100 + 3 («product ratio). After the blunt part of the box, 4 grams of expected leaven were obtained. Melting point = 1211: Prepared according to the above method • Prepare the 2-amine described in Table 2 below (please read the precautions before filling in this page) Η 楳 楳 Bi (CNS) IM regulation IM210X297 public) 81. 6. 10,000 sheets (H) £ 02448 bz. Ic. Λ 6 Ιί 6 5. Invention θ (3〇) Male ^ 2. T- (CH ^ )

T r4 r'4 m mp; 〇q -co2ch3 HH 1 231 -OH HH 2 121 -COO-CH2CH3 HH 〇175 -coo-ch2ch3 HH 1 162 -coo-ch2ch3 2-OCH3 4-OCH3 1 117-118 Preparation C 2-amine II 0 substituted by-(CH2) »-〇-C-) U or-(CDo-S-Xi- in the 5-position II ylthiazole Γ-amino-5-U-adamantyl-bucarbonyl Oxyethyl) -4-benzyl thiazole Μ 芍-\ 背 \ 而 1 η This page is decorated with thread by the Hube Biyang quasi-dipper = 5 Gongxiaozuo cooperative cooperative seal 31

A.4-U-golden alkyl "oxyl" -1-phenyl-1-butane-32- The standard of the paper is used in the standard a Hiis standard (CNS) IM specifications (21 (1: &lt; 2 listening public No) 81. 6. 10,000¾ (H) Λ 6 Π 6 ^ 02448 5. Description of the invention (31) (Please read the notes before writing this page) According to J. Org. Che ·, 1977, 42 , 8_, 1286, the absolute salt of 1-adamantyl carboxylic acid was prepared from 12 g of Bujin_ alkyl carboxylic acid and 10.96 g of broken acid. Dissolve the obtained K in 70 ml of DMF And then add 18 g of 4-iodo-buphenylbutane-buone. The reaction mixture was refluxed overnight. DMF was evaporated under vacuum, and the residue was resuspended in 5% Na2C0s solution and dichloromethane ( CH2CU extraction. After the organic phase was soaked with water • Na2S〇4 was dried. After concentration under vacuum • The residue was colored and analyzed on silica gel • Dissolved etched: CH2CU. The pure part was concentrated with 10 g of the expected compound. B .2-Amino-5-U-gold W alkyl-1-feroxyethyl) -4- $ yl_ 畦. Dissolve 10 g of the compound prepared above in 100 ml of tetragasified sulfonate (CCU). Add 4.9 g of bromine water dissolved in 50 ml of carbon tetrachloride. Let this reaction mixture stir for 30 minutes After washing with water, the organic phase was decanted * MgS was placed (U dry flashing * after filtration * concentrated under public space. The residue was dissolved in 50 «l 95 ° ethyl acetate>. To this solution was added 3.9 g of carbamide and let The reaction mixture was allowed to stand at room temperature for «night. After the mixture was concentrated in public space, the residue was dissolved in CH2CU and washed with 5% sodium bicarbonate (NaHC〇3) solution. The decanted phase was decanted and left to dry with MgS0. Ene, "After filtration • Yuxing empty box. Residues are dissolved in ether and dry olefins" Bi Yang, Ministry of Economic Affairs ^ &quot; JM Gongxiao 1,1 ·· Cooperative Du Yinhong Weight = 6.8g

Melting point = 1671C. Prepared according to the above method • Prepare 2-aminothiazole as described in Table 3 below. -33- 81. 6- 10, 000 sheets (H) This paper is used in a small format a S home furniture (CNS) TIM specifications (210X297 public) ^ 02448 Λ 6 η 6 V. Description of invention (32 ) Table

| -o- (ch2) 2 丫 Νη2 ° er ^ N Ministry of Economic Affairs, quasi-AM industrial consumer TV cooperation Du Yin ¾

Preparation I) 2-Aminopyrazole substituted with-(CH2) _X group at the 5 position • where X represents -3 4-The standard size of the paper on the paper side (CNS) IM specifications (2〗 〇x297 Publicity) 81. 6. 10,000¾ (H) (please read the back-to-back precautions ## to write this page) Installation · Order-line · ^ 02448 Λ 6 Β6 Ministry of Economic Affairs, 屮 央 柃 Apple Λ7Ώ: 工 消 1Ϊ · Cooperative printing 3i V. Description of the invention (33)-HLXz base · Χι = Χζ = Η. Preparation of 2-amino-5-aminoethyl-4-phenylthiazole (I): Ri = H · Riv = -CeHe »Rv = -CH2CH2MH2 AH-phthalimide-1-phenylbutane- Bu Si 27.4 g of 4-iodo-p-phenylbutane-p-one and 27 g of potassium phthalimide in 100 ml of DMF at 120 t: heated for 2 hours. DMF is concentrated in vacuum • The residue land mine is washed with water and IN NaOH solution and taken with acetic acid ethyl ##. After decanting the organic phase • After placing MgS0 «Dry suspected and filtered, edited by Yu Yucong. The amount of seal = 11 grams B) 2-amino-5-phthalosimine ethyl-4-phenylthiazole. Dissolve 9.6 g of the compound prepared above in 50 μl of tetrachlorocarbon and 80 ml of dicyanomethane. To this solution, add a solution of 5.6 grams of bromine in 30 liters of molybdenum tetraoxide. After the reaction mixture was washed with water, the organic phase was placed in MgS0 «乾 丰. 纆« Lu, and then it was condensed in vacuum. The residual gunpowder was dissolved in 70 ml of ethyl yeast and 4.5 g of urea was added. The reaction mixture was allowed to stand overnight in the chamber. After the mixture cools, use bromide to separate the filter, wash it with ethanol, and stir vigorously in 5% sodium carbonate / ether ether mixture. Will crystallize every filter. Xi Tan = 8g Melting paste = 208t: C) 2-amino-5-aminoethyl-4-benzylthiazole. Treat 8 g of the product prepared above with 1.5 g of hydrazine hydrate dissolved in 100 ng of absolute ethyl yeast. The reaction mixture was refluxed overnight, and then performed the following operations: B> The solution was concentrated in vacuo, and the residue was dissolved in water · Yi You was added by Ba Huan-35- Scale Side, with a clear rule (210x297 g; ":) ' R,, 1Λ ηη (please read # 背 而 &lt; Precautions before writing this page) Binding-bookmaking, 202448 Λ 6 Π6 V. Description of the invention β4) acidify to out = 1, digging a dione Separate the filter and cool the water phase on the ice bath. • Add the concentrated sodium hydroxide to the solution = 9 to filter the precipitate. After washing with water, dry it in the oven. Weight = 3.7 g Melting point = 136-137¾ Balance E 2-aminothiazole substituted with-(CH2) · X group at the 5-position, where X represents -ΝΧιΧζ group, where) U = H and X2 = -C. -CH3. 2-amino-5- (2-ethylhexyl-1-ethyl) -4-phenylthiazole. (I): Ri ^ H; Riv = -CeHB; Rv = CH3C0MH (CH2) 2-1 g of 2-aminohexazole obtained according to D for the preparation, dissolved in 60 ml of THF, in the presence of 0.7 ml of triethylamine , Treated with a solution of 0.44 ml of acetic anhydride dissolved in 20 «THF. The reaction mixture was allowed to stand at room temperature for 2 hours and shrank in the air. The residue was washed with 5% sodium bicarbonate solution, and Shen Yiwu was filtered to separate the water. After washing with water, dry the alkenes. Weight = 1.12 g Melt viscosity = 208-209Ό Using 2-aminothiazole obtained according to Preparation D, the bismuth was prepared according to the method of preparation of E • An intermediate compound described in Table 4 below was prepared. (Please read Jibei &lt; Notices # 冦 write this page) Printed by · Line · Printed by the Ministry of Economic Affairs, semi-AM industrial anti-crime cooperatives-36 T4 Gong imitation (2K1X29V male dragon) 81. 6. 10,000 sheets (H) c, 〇244e Λ 6 η 6 V. Description of the invention (55)

Η Ν 丁丁 Melting point V ° C ch7-oc-nh- 3 II 157-158! 1 0 ch3 1 CH ^ -COC-NH- 3 1 II oil I π ch3〇ch3-ch2-nh-c-nh- 171 o CH ^ -CHn-NH-C-NH- 3 z II 151 11 s (please read the notes first # 蜞 write this page) The Ministry of Economic Affairs, Pyongyang Huping, XJH, Gongxiao, Co-operation, Du-Industry 2- MF according to the group -4,5-di g-[5,4-d] -thiazolo- [1] -swiggling complex 1 1 one ... —- — — — / — \ .S., ΝΗ, (in

N / The size of the paper is used in the Hffl family (CNS) &gt; fM specification (210X29 / Public) 81. 6. 10,000¾ (H) 202448 Λ 6 Π 6 V. Description of the invention (5δ) AM-A-4 -2Η-3.4-dihydro- [1] -benzotoxin-5_ is based on 〇Fontaine, P. Maitte, CR Acad. Sci., 1964, 258. 4583 checks and balances. B) 2-amino-4,5-dihydro- [5,4- {1] -thiazolo- [1] -benzo hybrid leather. 2.05 g of thione was added to 0.027 moles of brominated derivatives dissolved in 100 ml of ethyl yeast. This mixture was refluxed for 3 hours. Evaporate the residue of ethyl yeast * into the aqueous solution of sodium sulfonate. The organic phase was extracted with ethyl acetate and the organic phase was dried and evaporated to dryness. Obtained 2.4 g of white crystals ° Melting point = 216t: prepared for 2-aminopyrazole substituted with-(CH2) »-X group at the 5 position of G * where = 〇 and X represents (Ct-CiJ alkoxy or halogen (Please read 1? Contrary to legal matters before writing this page hard) Binding-Order · Thread-Ministry of Economic Affairs: Yang, Ping, and Gongzhong Zhong cooperated with Du to print this paper, and use Zhongming ffl's home ttiMCNS) TM specification (210x297 male dragon) 10,000 sheets (H) 2,02448 Λ 6 Π 6 V. Description of the invention (37) Reaction process COCH2Br

COCHO

r4 HO-N;, c2h5 c2h5

r4 According to J. Org. Chem., 1977, 42 (4), 754. (Please read the notes on the back of this page firstly, Sun Wei wrote this page) Step 2

OCH COCHOCl-Si-iCH;) CH3〇H r4 According to Synthesis, 1983, 203. OCH3! CO-CH! OCH,

CO-CH〇CH; .4-.

Br

CO-CH equipment · line ·

CH-, COBr

OCH r4 r4 According to: J. Chem. Soc., Perkin I, 1981, 2435. -39- This paper is used in the edge of the home (CNS) »H specifications (210X297 public) 81. 6. 10,000¾ ( H) Λ 6 Β6 202448 V. Description of the invention (58) 2-amino-5-methoxy-4-phenylthiazole. (H) * Ra = H * Riv = ~ CeHs * Rv = ~ 0CH3 Mix 15.65 g of 2-bromo-2-methylamino-1-phenylethanone and 5.52 g of sulfur in 7 0 «L of formazan. The reaction mixture was refluxed "night" and then vacuumed. The residue is dissolved in a 10% aqueous solution of sodium triacetate. * This mixture is extracted with two embankments. After the organic phase is separated, successively put bowls of sodium bicarbonate to dry. After filtering, Xing Kongxiao is suspected. The residue M isopropyl ether was recrystallized. Heavy weight = 7.5g Melting point = 96¾ Dissolve the Burmese Armor in the dim thick atmosphere, (please first | «1. Read the back and pay attention to matters # 蜞 write this page) table

Ministry of Economic Affairs lr: 芈 ：： 工 消 f, '· Cooperative Du Yin ¾. "4 Melt Sticky 7 3C 2-C1 72 2-OCH3 159-160 4-CH3 112-114 Preparation Preparation of H Indole Carboxylic Acid : This paper standard is used in the S «Household iMCNS) T4 regulation (210x297 public release) 81. 6. 10,000 sheets (H) 2,03 ^ 48 Λ 6 Η 6 Ministry of Economic Affairs 屮 央 桴;! Tr- ^; M Gongxiao 1V · Cooperative Duin 3i V. Description of the invention (39) A) Bu third butoxycarbonylmethyl indole-2-carboxylic acid. A) Indole-2-carboxylic acid benzyl sulfide. 5 g of N , N'-carbonyldiimidazole was introduced into a solution containing 5 g of indole-2-carboxylic acid and 50 ml of anhydrous tetrahydrofuran; after stirring at room temperature for 12 hours, 3.7 g of benzyl yeast was added. * This reaction was heated at its reflux temperature ; The latter is steamed under reduced pressure to remove the cocoon. _ Maintain reflux for 8 hours. The residue is dissolved in ethyl acetate. The organic phase is washed with a 1N aqueous solution of sodium oxide and dried before the cocoon evaporates. Yellow residue Μ isopropanol recrystallization. Melting point = 136t: Yield = 85% b) l- the third butoxymethyl «I indole-2-salicylic acid benzyl chloride 80% hydrogenated sodium oil suspension (0.075 mole; 2.25g) Under cyanide, between (^ -51), add to the Indole-2-carboxylic acid benzyl ester (0.072 mol; 18.18 g) in 200 liters of dimethylmethanilamide solution. Allow the mixture to equilibrate to room temperature again, and stir the mixture for 1 hour. Then at lOt: dropwise Bromo-acid tertiary butyl amine (0.072 mol; 14 g). The reaction mixture was left at room temperature for 3 hours. The dimethylformamide was distilled off and the residue was dissolved in water successively. After extraction, the organic phase was allowed to dry and evaporated. The residue was crystallized with diisopropyl ether. 23.8 g of white crystals were obtained. Melt viscosity = 95 * C c) Bu third butane carbonylmethyl indole -2 -The carboxylic acid prepared above (0.065 μM; 23.8 g) is dissolved in 400 liters of ethyl yeast (please read the backing notes beforehand #fill this page) -41- This paper is used for standard size. Standard (CNS) 1? ^ Duo grid (210x297 ambassador) 81. 6. 10,000¾ (H) 202448 Λ 6 Η 6 V. Description of the invention (4〇) and 100 ml of a mixed solution of dimethylmethanamine. Added 1 gram of Pd-c, the mixture was boiled at room temperature under atmospheric pressure. After stirring for 30 minutes, the theoretical volume of hydrogen was adsorbed. The catalyst was filtered on talc and the molten steel was evaporated to dryness. The residue was crystallized, which was washed with diisopropyl ether. 15.3 g of white crystals were obtained. Melt viscosity = 177¾. B &gt; 1-Ethylindole-2-carboxylic acid. Containing vermole-2-smilic acid (0.06 M Ear; 10 g) · triethylamine (0.15 mol; 21.25 g> M anhydride (0.07 5 mol; 7.5 g) and 4-dimethylaminopyridine (0.0 06 mol; 0.8 g and dimethane The mixture was stirred at room temperature for 18 hours. Then the reaction mixture was poured into an aqueous solution of 2 buried burial. After the formed sediment is filtered, it is dried in a vacuum oven. Decant the dichloromethane phase, place in a bowl and let dry and steam to 3/4 weight. The second product is the indole-2-carboxylic acid precipitate. Mix the two harvests • 9.4 grams of gray crystals are obtained. Melting point = 168¾ C) 1-benzyloxypyridinamine-2-carboxylic acid Dissolve 8 g of indole-2-carboxylic acid in 120 ml of dichloromethane • Then add 10 g of triethylamine and 1 g of 4-dichloromethane Methylaminopyridine. This reaction mixture was cooled to after stirring. At a temperature of less than 5 t, 8.5 g of benzyloxycarbonyl chloride was added dropwise. Let this mixture play "Ye ·" and then Xingkong under the thick dysprosium. The residue was dissolved in 500 «L of ethyl acetate and then filtered. The mother liquor was concentrated under public opinion and dissolved in 50 mL of dibin methane. Mother liquor «« After the Yu Yukong down to Nongpu. (Please read-! · **? And · Notes for A before filling out this page) Binding · Binding- Line. • 4 2-This paper is used in the standard side ®®Kasabi (CNS) T4 specifications (2) 0x297 male; Sb) 81. 6. 1〇, 〇〇〇 Zhang (Η) 202448 Λ 6 _Π_6_ V. Description of the invention (Μ) Weight = 2.4 grams of oil HHR (DHSO): 5.38 (2H, s. ClU- CeHs); 7.0-8.0 (10H,. Har) 0 du-Third-butoxymontyl indole-shaped-carboxylic acid 30 ml of a solution containing 6 g of disulfonic acid di-tributyric acid was added dropwise to 30 liters Contains 4 g of indole-2-carboxylic acid, 4 mM triethylamine and 0.4 g of dimethylaminopyridine in an ethyl acetate solution. Stir at room temperature for 2 hours and remove the precipitate formed * The residue removed by steaming in Yiqizang is dissolved in methane. After washing the organic phase with water, it is dried and concentrated to dryness. Melt adhesion = 117 t: Yield = 66¾ «Example 1 2- [(2-Indolyl) carbonylcarbonyl] -4- (2,4-dimethoxyphenyl) -5-benzylthiazole ( (Please read the notes beforehand to write this page)

The Ministry of Economic Affairs of the People's Republic of China, the Ministry of Economic Affairs, the Ministry of Economic Affairs

Ry = -CH2-C6H5 t; 1.96 g of 2-amino-4- (2.4-dimethoxyphenyl) -5-benzylthiazole * 1.22 g of 1-vinyl indole prepared above according to Preparation A Indole-2-carboxylic acid · 0.85 g of triethylamine and 2.95 g of BOP, dissolved in 20 liters of dimethyltinamide. The reaction mixture was stirred in the room for 24 hours, and then poured into a solution of grade 2 = solution. The yellow precipitate was separated by filtration, washed with water, and dissolved in ethyl acetate. This -43- Each paper 5 Min Fan Du Xiao used in the HB home sample standard (CNS) T4 standard Dai (210X297 mm) 81. 6. 10,000¾ (H) £ 02448 V. Description of invention (&amp; 2) Solution land cable Use a retarding solution = 2 * water • wash with 5% sodium argonate solution and water, then dry with HgSO * and concentrate under vacuum. The residue was analyzed and purified by coloring mushrooms on silica gel. Dissolving agent: dimethane / ethyl acetate 98/2 (M product ratio). The pure product was partially concentrated to obtain a residue, which was treated with a solution containing 3 g of 2 (: 〇3 to 80 ml of formazan for 24 hours. The formazan was stirred in a vacuum soil, and the residue was dissolved in water / ether mixture Liquid. The white sinker β is divided into two and washed with a bond of 9 resuspended = 0.97 g melting point = 201 -202 υ (please read back to the precautions # fill in this page) according to the compound of the present invention, its It is described in the following table 6 and produced by the following method. It is the same as the M. Square. Thread. Thread. Ministry of Economic Affairs: 揮 央 惃 准 x;: cx 工 消 作 作 社 社 Printed 3i 44-81. 6. 10,000 sheets (H) Originally recognized as 5 good standards Happy Use of Chinese Η Family Completion (CNS) &gt; fM Regulations (210x297 Concession) ^ 02448 Λ 6 Π 6 V. Description of Invention (^ 3) Constitution 6

N Η

H, CO OCH Ministry of Economic Affairs Standards and Standards =? Work elimination cooperation Du Yin 31 ^ Example number RV Melt adhesion 7 3C 2, ch: O 225 3 &lt; 〇 &gt; -1 / 〇CH3 272 4 262 5 ^ ^ Sdch3 225 6 V och3 283 -45- This paper is used again and again. S Η Family Standard (CNS) ΤΊ specification (210x29 / degrees) 81. 6. 10, 〇〇〇 Zhang '(H) (Please read first Contrary to the precautions, please fill out this page) Packing · Ordering-Line · £ 02448 Λ 6 Β6 Economical Beiyang, Yangqin, Qin, Mong, Consumers, Cooperation and Cooperation Du Yinyu 5. Description of Invention (¥ f) Example 7 2- [ (Bu third butoxycarbonyloxymethyl-2-0¾ indolyl) carbonylamino] -4-benzyl-5-hydroxyethylthiazole. (I): Rv =-(CH2) 2-0H; Rlv = -CeHs; Ri = H;-2! CH2C〇2C \ CH3) 3 2 g of the amino alcohol prepared above (according to Preparation B, Table 2) · 2.75 g of the third butane carbonyl indole-2-hydrophobic acid, 1.4 g of triethylamine and 4.9 g of BOP were dissolved in 15 ml of dimethyltinamide. Let Dong * at room temperature overnight, pour this reaction mixture into the emulsified phosphate phosphate solution, the output = 2. Separate the Shenjiao by side filter, wash with water, and dissolve in ethyl acetate. This solution was separated by decantation with a 5% »13 1 ^ 〇3 solution and a water-washed * box. The eaves phase was placed on MsSOe and dried and concentrated in Xingkong. The residue was purified by color analysis on silica gel. * Dissolving agent: dichloromethane / formaldehyde 100 + 0.5 (volume ratio). The first poloxane product dissolved out is equivalent to the de-enylated compound (0 and N yin • melting point = 70TC). The expected product was dissolved by the second slang. Reset = 1. 2 g Melting point = 180-1811 Ben Example 8 2-[(1-Third-butoxycarbonylmethyl-2-indolyl) pyridyl] -4-phenyl-5-68 acid Ethylthiazole (please read the precautions before filling and writing this page) Binding and Ordering Line--46- This paper size is common to China S Jiayu Bi (CNS) T4 stack tM2] 0x2i) V male dragon) 81. 6. 10, 〇〇〇 Zhang (H) S02448 Λ 6 I? 6 V. Description of the invention (45)

(I): R, = Η; Z

R IV-= -CsH5; Rv * CH3-COO- (CH2) 2- CH2C〇2C- (CH3) 3 The Ministry of Economic Affairs levies 0.30 g of the product prepared above from the quasi- ^ industrial and consumer cooperation Duin grade 5ml of pyridine. 1.2 ml of _anhydride was added, and the reaction mixture was stirred at room temperature overnight. Then pour the mixture into a sulfate retardant solution of = 2, thinly filter the sediment, wash it with water, and dissolve in methylene chloride. This solution was washed successively with 5 96HaHC03 solution, and the decanter was decanted and separated. The organic phase was dried with MgS0 «, after side filtration, it was concentrated in vacuum. The residue was passivated by silica gel color layer analysis. Dissolving agent: dichloromethane / ethyl acetate_98 / 2 (touching ratio). Heavy weight = 0.16 g NHR (DMSO): 1.48 (9H, s, t-Bu〇2C); 2.00 (3H, s, CH3CO2); 3,24 (2H, t, J = 71U, CH2thiazole ; 4 · 3 0 (2 H, t. J = 7 fU, CH 2 0 A c); 5,40 (2H, s, CHzCOzt-Bu); 7.2-7.9 (10H, b. Har); 12.8 (1H , s, NHCO) 〇 «Example 9 2-[(l-carboxymethyl-2-indolyl) quasi-amino] -4-phenyl-5-» acid ethylthiopyrene 〇47- Original paper 5lt scale In the use of the "« home sample standard ([吣) 1 »4 specifications (2 丨 0> &lt; 297 public:« :) 9 Read the details before writing this page 81. 6. 10,000 sheets (H) £ 02448 Λ 6 Π 6 V. Description of the invention (46) (I): Ri = Η; Z =; RjV =; Rv = CHyCOO-CCH〗),-

CH2C〇2H 5 g of the compound prepared above was dissolved in 2 ml of Benjia 81 and 10 trifluoro-acid. The mixture is placed in the room pan for 45 minutes ’and then placed in the Yukongxiao box. The obtained residue was washed with a mixture of n-hexane and ethyl 50 (50/50>) and dried. Reset = 0.14g melting point = 217-218t: real cell example 10 2-[(1-ethyl alcohol- 2-Echlamido) quasi-amino] -4- (2,4-dimethoxyphenyl) -5-ethoxy stage methylthiazole ° (I): R, = H: Z:

RIV h: R 、. = (ΓΗ; (ΓΗ ， -ΟΟΟ · 0Η ，-(please read 邠 背 and ^ Notes and fill in this page first) 装 · 定 _ 线-

N The Ministry of Economic Affairs Standards for the AM Industry & Cooperatives will print 1.5 g of 2-amino-4- (2,4 ~ dimethyl gas phenyl) -5-ethyl gas carboxymethyl, 1 g 1- Ethyl lumbendo-2-carbonyl acid 0.7 L triethylamine and 2.39 g BOP were dissolved in 15 ml dichloromethane. The reaction mixture was stirred in the room "Night, then Yu Xingkong shrank." The residue was dissolved in ethyl acetate, and this solution was used as a grade 2 solution, washed with 5% NaHC03 solution and water, and then organically dried with MgS0 &lt; t and condensed in Xingkong. The residue is colored on silicone 48. The paper is used on a scale of 01. 81 81 Standard (CNS) TM (210X297) 81. 6. 10,000 sheets (H) 9% 03448 Λ 6 Π 6 V. Description of the invention (47 ) Analysis and purification of tantalum, dissolved ion: dichloromethane / acetate acetate 100 / 2.5 (granium ratio). Weight = 1.2g Melt viscosity = 130-135 t: Example 11 2-[(2-Indolyl) carbonylamino] -5-ethoxycarbonyl-4-phenylthiazole

(I): R, = Η; Z

R IV =-C6H5; Ry = CH3CH2-〇CO- read ir to the contrary · Notes and then write this page Ministry of Economic Affairs 屮 央 榀 平 々 = :: 工 消 盗 合作社 印 51 According to the embodiment 10 described above The method was prepared to obtain the compound 2-[(1-ethynyl-2-indolyl) carbonylamino] -4-phenyl-5-ethoxycarbonylthiazole (1.5 g) and was present in 0.6 g Na2C03 Dissolve in 100 liters of ethyl yeast. The mixture was stirred at room temperature for 48 hours. It was then concentrated in vacuo. The residue was milled in water, and then the smallest dichloromethane was added, and it was dried after filtration. Weight = 1.1 g, melting point = 248¾ ff Example 12 2-[(2-Indolyl) amido]- 4- (2,4-Dimethoxyphenyl) -5-carboxymethylthiophene.

(Γ): R. = H: Z N! Η = ί | η 丨 Human power.

OCH,; Rv = -CHt-COOH OCH · 49- This paper is used in the "« Home Standard (CNS) T4 specification (210x297); «:> 81. 6, 10,000 sheets (H) £ 02448 Λ 6 Π 6 5. Description of the invention 0.5 g of 2-[(l-ethosyl-2-indolyl) carbonylamino] -4- (2,4-dimethoxyphenyl) -5 prepared according to Example 10 above -Carboxymethylthiazole, dissolve it in 10 ml of 95 ° ethyl acetate * and then add 1.5 mL of 2N NaOH. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in U = 2 Street solution, the precipitate is separated by filtration, washed with water, filtered, and then washed with water. Weight = 0.28g Melting point = 284t: Prepared according to the method of Examples 7-12 above * Prepared as described in Table 7 below Compounds. Ih read tr the other way round-note the notes and write a copy of the book π to the standard of the Ministry of Economic Affairs and to be printed by the Cooperative Society ¾ This paper is used in the standard "8) Family Sample Standard (〇 肊) 肀 4 regulations (2 丨 0 &lt; 297 public announcement) 50-81. 6.〗 0,000 sheets (H) ^ 02448 Λ 6 U 6 V. Description of the invention (49) m

c NH-C, W A i .1 U

N

Rc ϋ Standard of the Ministry of Economic Affairs-? 3G printed by the Mongong Consumer Cooperative Society No. 1 Brick 1 T m r9 Melting point; eC 13 -CO2CH3 1 H 254 14 -co2ch3-&gt; H 181 15 -OH 2 -ch2co2h 131 16- OH 2 H 242 17 -OH 3 H 213 18 .-OCOCH3 2 H ---- 168 19 -OCOCH3 3 H 192 20 -o-co-c6h5 2 -ch2co2h 216 21 -O-CO-ierr-Bu 2 H 229 22 -CO2H 1 H 260 23 -CO2H 2 H &gt; 300 24 -CO2H 2 -ch2-co2h 239-240 25 -CO2H 1 -CH2-C〇2H 199-200 -51- (please read the notes and ^ Notes first (Further writing this page) 5fc scale of this paper is used in the detailed specifications of the H countries (210X297 ministers) 81. 6. 10,000 sheets (Η) 202448 Λ 6 Π 6 V. Description of the invention (5〇) Table 7 (New York) I Example number D m Rg Melting point,-eC, 26 -co2ch3----ch: -co2h 202-203 27 -co2ch3 1 -CH, -CO, H 183-185 28 -CN- (CH3) 2 丨 1 1 -CH2-C〇2H 252 0 Η 29 -CN-CH ... 1 l -CH2-C〇2H 233-234 〇30 1-0 l -ch2-co2h 241-242 0 Example 31 2-(( 2-Indolyl) carbonylamino] -4-phenyl-5- [2- (1-pyrrolidinylcarbonyl) -1-ethyl] thiazole. : Please read the precautions before filling in this page) Installation · Thread · Ministry of Economic Affairs, Central Standards · Α Η Industry and Consumer Cooperatives printed 5i (I): R, = Η; ZO people I Η; Rjy = -CgH ^; Ry =-((ΓΗ:):-.. '| 52 This fcUfc scale is used in the SH family's home (CNS) T4 regulation (2) 0X297; ":) 81. 6. 10,000 sheets ( Η) Λ 6 II 6 ^ 02448 5. Description of the invention (51) Add 0.5 g of the ester described in Example 14 to 5 ml of pyrrolidine. The mixture was stirred at room temperature overnight. Then it was poured into pH = 2 The precipitate is separated by filtration and then dissolved in ethyl acetate. This solution is washed with a slow-balanced solution of = 2, and then washed with water. Separated by decantation. After drying with MgS〇4, Concentrate in vacuo.

Weight = 0.48g Melt viscosity = 179TC According to the method of Example 10 above, the compound 32-51 is prepared as described in Table 8 below. 9 7 ^. Please read it, back to the back. Notes to re-write the gutter standard of the Ministry of Economics ^: ^ Gongxiao imitation cooperatives printed 51 -5 3-This paper is used for the standard side Η Η 家 楳 准 (CNS) ΤΜ Specifications (210x297 public) 81. 6. 10,000¾ (Η) 202448 V. Description of the invention (52) Λ 6 Η 6

Example number τ m Γ4 Melting point;% (please read the notes to the back before writing this page) -cooch3 -cooc2h5, c2h:

-N c2h5 -C-NII 'o / -C-NIIo The Ministry of Economic Affairs is looking for the right and the work is printed by the cooperative ¾ -C-NII vo -NFh NH-C-CH-II. O 2 2

4-F 2-CI HH 4-F 2-CI HH 224-225 178 180 239 243-244 187-188 202-203 261-262 Gutter-5 4 This paper size is used in the middle of the 8-sleeved home standard (CNS ) ^ M specifications (210x297 male dragon) 8L 6,] 〇, 〇〇〇 Zhang ⑻ ^ 02448 Λ 6 Π 6 V. Description of invention (53) Table 8 (mm) Ministry of Economic Affairs Du Yin 51 Example No. Ma | T m \!; ^ • i 1 i 1 I melting point .; ec t-40 -oc-ch3 • i) 4-F 188-kS ^ 41 〇-OC-OCH, 丨丨 2 H 208-209 42 II 〇-NH-CO- ^ rr -Bu II 2 H 223-224 43 II 〇-NH-C-0-CH- ;, 1 J II 2 H 264 44 II 〇HI -NH -C-N'-C7H ^ 丨 丨 Z 3 2 H 248-249 45 II 〇-NH-C- (CH9) 9-C09H 11 "-2 H 275-276 46 II 0 H 1 -NH-CN-C2H5 2 H 209-210 47 2 H 196-197 48 -OC * 0 och3 OCH ^ 2 H 218-219 -5 5 _ 81. 6. 10,000 sheets (Η) (please pay attention to the precautions before WW and then copy this book Page) Binding · Thread · 20344B η 6 V. Description of the invention (54) Table 3 (mm)-a 丨 Example number Τ m Γ4 ί i Melting point; eC t 1 49 CH} 丨 .. Bian-prepared τ Η 1 UO-142 50 〇 / ch3 • 〇-C- &lt; g) -CH3 〇τ Η 270-271 51 2 Η 212-213 (please read back to the precautions # 蜞 write this page) Example 52 2-[(2-Indolyl) carbonylamino] -4-phenyl-5-anilino-carbonyloxyethyl Thiazole

(I): R, = H: Z 1

Ν · 丨 Η β, &lt;

Economically, the central quasi-industrial fi's co-printed A) 2- [U-ethinyl-2-indodoyl)]] amino-4-phenyl-5-anilinecarbonyloxyethylthiazole. 0.75 g «Drunken and 0.2 liter l-dibenzyl cyanate» prepared according to Example 16 at the room temperature in 5 «L diazomethane </ b> night. The precipitate formed was separated by filtration, and then purified by chromatography on a silica gel. The dissolving agent: diazomethane-5 6-81. 6. 10,000¾ (Η: S02448 82.12.22 V. Description of the invention (55) / Acetyl acetate 95/5 («Specific gravity man = 0.52g melting point = 1561C B) Compound 52 0.5 g of compound prepared in ± surface * dissolved in 30« L ethyl acetate and 5 L water • Then add 0.21 g Ha2C〇s »'This violin_mixture was stirred overnight at room temperature • Then concentrated in the empty space. The residue was dissolved in ethyl acetate and washed with ITa2C〇3 solution and washed with water. The phase was separated by decantation and concentrated in vacuum Shrink. The residue is dissolved in the B bond. Weight * = 0.4 g Melting point = 2491C Example of sack 53 2-[(2-18 丨 D mining base) sacrificial limb base] -4,5-diS- [5 , 4-d] -lH -Sleep Acene

And mixed leather. (I): R, = Η; Z Ν I Η (please read the back of the pill first · &gt; i.Importance νφfill • write this page); Rv and RjV = 0- (CH2)-&gt;-

Μ 浒 部 屮 楮 汓 β 揓 工 消 1V · Cooperative cooperative printing 31 1 gram of thiazole prepared above (preparation) * 2.6 g &amp; 0,0.93 g of ethylpyridinyl "I-dole-2-number acid and 0.46 g of triethylamine, mixed in 30 liters of dimethyltamide. The reaction mixture was broadcast at room temperature for 30 hours. After dimethylformamide was evaporated, the residue was dissolved in ethyl acetate and washed with water. There is a coherent phase of sodium naphthenic acid after evaporation. Chromatographic analysis of the residue on silica gel, dissolving agent: dichloromethane / methanone 100 + 0.5 (accumulation ratio). Obtain 0.9 g of yellow foam. Dissolve the foam in it and add ethyl yeast (100 liters) of dihydromethane 57. This paper ΛΛϋ is used in the sleepy home «UMCNS) 1Μ regulation« (210x297 public *) 81. 6. 10,000ft (Η) Λ 6 Η 6 V. Description of the invention (56). 10 ml of 2H NaOH was added, and the filling chamber was stirred for 1 hour. After the organic solvent cocoon evaporates, the residue is dissolved in ethyl sulfonate and used to dissolve the solution of tang = 2. Set with the eaves MgS0 "Dry and then" filter and steam to dry "to get a yellow knot • Then use two" [methane soo • re-washed with ethyl yeast "Weight = 0.45 grams of melting" &gt; 260t: Ben pickling example 54 2-[(2-Indolyl> Carboxamido] -4-phenyl-5- (1-hexahydropyridyl) thiazole (please read first? 5? Contrary to this, the code can be written on this page)

According to the standard of the Ministry of Economic Affairs: Γβ printed by the Cooperative Society A) 2-amino-4-phenyl-5- (1-hexapyridyl) thiazole will contain 1 gram of 2-amino-4-benzene The mixture of 5-bromothiazole, 1.7 g of hexahydropyridine and 25 ml of absolute ethyl acetate was refluxed for 48 hours. The yeast is concentrated under vacuum. The residue was dissolved in 50 ml of water and 10 μl of 30% Ha0H. After extraction with ethyl acetate • The organic phase was placed with Na2S0 «dryene and filtered. The solution was concentrated in vacuum with dysprosium, and the residue was recrystallized with propyl ether. Amount = 0.41 g Melting point = 135-1 37t: B) Compound 5 4 0.4 g of the product obtained below was dissolved in 50 mg of diazomethane. Lu Ji added 0.33 g of 1-ethynyl indole-2 -carboxylic acid. 0.82 g of B0P and 0.19 g of San-58- ft scale of this paper was used in the middle «Home Sample Apple (CNS) IM regulations (2) 0: &lt; 297 public; ¢) 81. 6. 10,000 sheets ⑻ ^ 03448 Λ 6 Η 6 V. Description of the invention (5?) Ethylamine. The reaction mixture was stirred at room temperature for 4 days. Add 25 ml of water and separate the organic phase by thin decantation. After drying with Na 2 SO 4, place in a vacuum soil box. The residue was dissolved in 50 ml of absolute yeast, and 10 «L of 2.5N NaOH was added, and the mixture was stirred at room temperature for 3 hours. After the mixture was concentrated in Xingkong * The residue was dissolved in 50« L of water and extracted with ethyl acetate * There is 抇 柏 擊 擊 擊 @ · After placing Na2S0 «after dry flashing, put it in a vacuum soil box. The residue K was recrystallized from ethyl acetate. Weight = 0.26g Melt adhesion> 260 * C According to the method of * Example 54, the compounds 55 and 56 described in Table 9 below were prepared.

RV \ ^ S NH-C- (please read the notes on the back # «write this page)

N i Η 9 Example No. 1 Rv Melting point J ° c 55 -NV〇H &gt; 300 56 / ~ \ 247-249 -N NC-0-CoHc \ _ / 1! ~ 〇-5 9 _ 遑 度 尺5) CN / V home (21 gH (V Zhang I 10 · 6 81 ^ 02448 Λ 6 It 6 V. Description of the invention (58) Example 57 2-[(2-indolyl) amine group] -5 -O-4-phenylthiazole.

(I): R, = Η; Z I Η; R [V =; Ry = Br, the Ministry of Economic Affairs, the central standard · / ί ;; A industrial consumer cooperation Duin 5i will 3.9 grams (0.015 mol) of methyl chloride. Add 3.26 g of 1-ethylenium triethylamine. The reaction mixture is buried in a quarry to an aqueous solution of = 2. Na: * S04 is dry and leaven in the air. Then add 5 g of Na2C〇3 under vacuum. After shrinking at a low temperature, the liquid was extracted with ethyl acetate, and after «filtration, it was concentrated under the air. Face: CH2CU. After removing the top layer, dissolve it and evaporate it to 20 li = 2.8 g of melt paste = 224-226 C «Example 58 2-[(2-indolyl) carboxamido] -5 -methoxy Benzyl-4-benzylthiazole 2-limb-5-bromothiazole dissolved in 60 liters of diole-2-carboxylic acid. 8.1 g of this mixture was stirred in a room irrigator. . This mixture was dissolved in 100 organic phase residues. After pure matter, methyl chloride / 8 days, and then after decantation, the residue was dissolved in the room «rise slow balance Na2S〇4 ^ coloring of silicone rubber • expected to produce diisopropyl 8 * Β0Ρ · 1.85g after adding 100 milliliter, the organic phase was placed in 100ml of for 3 hours, and dissolved in water until pH = 2. Analysis of the hydrocarbon layer of the mixture, the lysate is dissolved by the sickle, and the recrystallized solution (please pay attention to M-ir first and then write this page) Binding-Order · Line · -60 This paper 5 people standard side "1 in "« Homewood (CNS) IM specifications (210x297 g; «:) 81. 6. 10,000¾ (Η) V. Description of the invention (59)

(I): R1 = Η: Z

Λ 6 Π 6: =-匸 6 latch 5: Rv = -〇CH: 3.15 g of 2-amino-5-methoxy-4-phenylthiazole was dissolved in 60 mL of CH2CU. Add 3.26 grams of ethyl ethene "I-dol-2-carboxylic acid, 8. I2. Grams of BOP and 1.86 grams of triethylamine. This reaction mixture was kept in the chamber for one week. After adding 50 ml of water, the eaves phase was decanted. After drying with Na2SO4, it was filtered and shrunk under vacuum. The residue was dissolved in 100 ml. Formazan • 10 g of K2C〇3 was added, and the conjugate was stirred sloppyly in the room. The mixture was concentrated under vacuum, the residue was dissolved in water, and the formed precipitate was separated by filtration and washed with CIUCU. Weight = 1.7 g. Melting point = &gt; 260t: Preparation according to the method of the above example * Compounds 59-61 described in Table 10 below were prepared. First read in Contrary Notes% Installed on this page η Line Ministry of Economics 搮 央 榀 准 / 'Jn 工 消 1V · Cooperate Duyin 3i -61-This paper standard is easy to use in the Ming Dynasty Η 家 榣 平 (CNS) T4 regulations怙 (2) 0x29 / Public) 81. 6. 10,000 sheets ⑻ 32. V. Description of the invention (g〇)

IQ

X Η-c —; l 0 Λ 6 η 6 Η

Example No. mp; ° C 59 2-C1 260-262 60 4-CH3 252-254 61 2-OCH3 j 248-250 Example 62 2-[(2-indolyl) carbonylamino] -5-hydroxyl * -4-phenylthiazole

V (I) R, Η; ZO

R

IV

• CgΗ ^; Rγ = -OH

N I H The Ministry of Economic Affairs, the Central People's Republic of China, X / M Industrial Consumer Price Cooperative Printing ¾

0.58 g of the thiazole prepared according to Ben Example 58 was dissolved in 100 liters (: 112 (: 12. Add 4.98 liters of 2 &gt; &lt; boron tribromide (^ 2 (: 12 dissolved in the room temperature. Let The reaction mixture was stirred for 24 hours. 4.98 liters of BB "3 were added again. The mixture was left at room temperature for 5 days. Finally, 4.98 grams of BBr3 was added. The mixture was left at room temperature for 48 hours. Then 4N HaOH solution was added. Adjusted to pH _ 6 2-This paper is used in the 5fc scale of the edge of a home standard (CNS) TM specifications (210X297) 81. 6. 10,000 sheets (Η) 448 Λ 6 Π 6 V. Invention description (61) = 5-6, and the supported phase was extracted twice with 50 liters of 4N NaOH. The aqueous phase was added with 2N HC1 solution to neutralize it. The mixture was extracted with CH2CU, the organic phase was dried with Na2S〇4, filtered and concentrated in vacuo , A crystallization residue is produced Ο Weight = 0.5 g Melting point = 237-239X: (please read first, please pay attention to Apple and then write this page) Binding-Order 'Line · Ministry of Economic Affairs 汮 央 満 准 x, ( : cr industry price cooperation Du Yin 51 63 original paper 5fc standard for the use of SS home standard iMCNS) TM regulation ί210 × 29 / public and) 81. 6. 10,000 sheets (Η)

Claims (1)

A? Drugs ... The application of "Zhenwuli" is a special application for Fan Zhaoxiu (year and month) C7 —------------D7 Six's formula for patent application (I) 2-Amidyl thiazole correction cries 1. 2 9 This year's cold 丨 1 prison Rv όπο 1-R.— ΝΥ—Ν S In the Central Ministry of Economic Standards-printed formula-1U represents a hydrogen atom; (Ci-CJ alkyl group or a stupid alkylene group with (Ci-Ca) alkyl group; formula -Za-NRds Amine alkylene group, where Zi represents (c2-c4) alkylene group and R5 form a saturated heterocyclic ring from a nitrogen atom connected to Η or (U-Ca) alkyl or respectively, selected from morpholinyl, Pyrrolidinyl, hexahydropyridinyl, hexahydropyridinyl and (Ci-C3) 4 -alkyl hexahydroalkenyl; formula -Z2COORe optionally esterifies carboxyalkylene groups, of which 2 represents (hU) The hydrocarbyl group represents Η or (Ci-Ce) alkyl; (C2-Cs) cyanoalkylene; the amino-methylene hydrocarbylene group of the formula-Z3CONR7Re, where Z3 represents (Ca- ") alkylene and 7 and R8 represent Η, respectively Or ("-") alkyl, or heterocyclic ring NR 4 R s with Ν; (C 2-C β) hydroxyalkylene, or (Ci-Ci.) Alkoxyalkylene;-RIV represents unsubstituted or (C3-C7) cycloalkyl substituted with one or more (Ci-Cd alkyl; aryl is selected from phenyl, which is unsubstituted or carries one or more substituents, this substituent is selected from Halogen atom, especially gas or fluorine, (Ci-Ce) alkyl, (Ci-Cs) alkoxy and thioalkoxy, nitro and trifluoromethyl, and .. heterocycles, which contain at least one heteroatom selected from 〇, S and Η, especially furyl Ithiophene Base, pyrrolyl, pyridine (please read the precautions on the back and then this page of Xiwo) f 4 (210X297 Kang)% 0 ^ 4¾8 A7 B7 C7 D7 VI. Applying for a patented oxazolyl, imidazolyl I pyridyl , Pyridinyl, oxazolyl and thiazolyl, which are optionally substituted with (Ci-Cs) alkyl or halogen atoms or (Ci-Cs) alkoxy or Rv and RIV together represent the following groups: P / nP is connected via a phenyl carbon at the 4-position of the thiazole ring and where u is equal to 1-3, optionally carrying one or more (np) substituent XP, which is the same or different, selected from halogen atoms, ((^-(: 3) alkyl and alkoxy, nitro and trifluoromethyl, ηρ is equal to 0-3; —— Rv represents-(CHzh-X group, where m is 0-5 and X represents • Halogen atom, preferably bromine atom, hydroxyl group, (C3-C7) cycloalkyl group, phenyl group which can be selected from halogen atom, (Ca-Cs) alkyl group or alkoxy group, or nitro | amino group • hydroxy group or Where one of the trifluoromethyl groups is substituted, _ is selected from -C00H; -COOXi; where -0-COX :; or -SC 0 X i; (0) q-S-X! Where Q = 0, 1 or 2 ; -O-COOXi; N-CO-Xi where X3 = H or (Ci-Cs) alkyl; HN-C-0-X -NH-C-NHXi where W = 0 or li II ow (please read the back Please pay attention to this page and then fill out this page) Printed s by the Central Bureau of Standards of the Ministry of Economic Affairs; -NH-C- (CH2) 3-C00H where s = 2,3,4 II o 2- f 4 (210X297 Koji) 844 η ο 7 7 7-AB c D Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 6. Patent application profile where Xi represents (Ci-Cs) alkyl; stupid can be selected by one or more Atomic atom, (Ci-C3) alkyl or alkoxy or nitro group, amino group * hydroxy or trifluoromethyl substituted; adamantyl group; selected from -CONXiXs; -NXiXz-group; wherein XiR represents hydrogen , (Ci-Cs) alkyl or stupyl which is unsubstituted or substituted by one or more groups, this substituent is selected from a halogen atom, (Ca-Cs) alkyl or alkoxy, or nitro, amine Group, hydroxy or trifluoromethyl substituted and χ2 represents an argon atom, (Ci-Cs) alkyl, or changed to 1 and χ2 and the nitrogen atom to which they are connected to form a heterocyclic ring, the heterocyclic ring is selected from pyrrolidine or Hydropyridine, which is unsubstituted or substituted with a monooxy group or a hydroxy group, the latter being unsubstituted or substituted with an acyl group or substituted with-(: 0 (^ 1 or-(: 0 "1 \ 2 group; or Love is more lUaa-Cs) alkoxy; hydroxyl; a cyclic amine with 5 or 6 members; it is unsubstituted or substituted by oxy or hydroxy; hexahydropyridyl, which is unsubstituted or substituted-COOAlk N-substituted, where Aik represents (Ci-Cd alkyl; carboxylic acid group, -NX2X4 group, where 5U = H or X4 =-(CH2) t-X5, t is equal to 2, 3 or 4 and X5 represents -0H , -O-CO-Rz &gt; -NHC0R2--HH-C-NHR2 where R2 represents (Ct- Ce) alkyl; or-NR2R3 group, where 1? 2 or 1? 3 respectively represent Η, (Ca-Ce) alkyl, stupid group which is unsubstituted or substituted by one or more substituents • This substituent is selected From a halogen atom or (Κ3) alkyl or (Ci-Cs) alkoxy, or R2RR3 and the nitrogen atom to which it is connected to form a 5 or 6-membered heterocycle: A 4 (210X297 public) ...... ................................................... 3t .... ......................... ir •…: &gt; .................. ... sf (please read the precautions on the back before filling in this page) 8442 ο 0Λ AB c D Printed by the Central Bureau of Economic Affairs of the Ministry of Economy VI. Applying for a patent Fan® Z stands for heteroatom containing one or more heteroatoms , The heteroatom is selected from 0, s and N, the heterocycle is coupled to an aromatic ring, the aromatic ring may also contain a heteroatom selected from 0, S and N and may be substituted by one or more groups , This substituent is selected from halogen atoms, (Ca-Ca) alkyl and alkoxy groups, or benzyloxy · nitro, amine groups and trifluoromethyl groups, the hetero atom N may be aromatic or N-NH form • It is unsubstituted or substituted by (U-C4) alkyl, carboxyalkylene-Z4-C00Rlo, where z4 Table 1 and ^ alkylene. Is Η, benzyl or (Cx-Ce) alkyl; aminomethan alkylidene-Z5-(: 0Νυ12, where r5 represents ((:!-") Alkylene and Rn and R12 represent Η, (Ci- Ce) alkyl, or form a saturated heterocyclic ring with N such as morpholinyl or hexahydropyridyl; acetoxy C0R13, R13 represents (C: -C Ο alkyl or phenyl; alkoxycarbonyl -C 0 0 R: 4 , Where R: 4 is a third butyl or benzyl group; Μ and the compound of formula (I) and additional salts of inorganic or organic acids and bases. 2. The compound of formula (I) according to item 1 of the patent application scope, Wherein Z stands for benzothienyl, benzofuranyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, quinolinyl, iso-DS-linyl, Ug-kelinolyl, oxazolinyl and [2 , 3-c] -thieno or [3, 2-c] pyridyl, isoindolyl or indolyl ', which is optionally substituted, and indolyl is optionally substituted on the nitrogen (Ci- Cd alkyl, carboxyalkyl-Z4-C00R1o substituted, which represents (Ci-C ^) hydrocarbylene and R10 represents η, benzyl or (Ct-Ce) alkyl; aminomethylammonium-Zs-CONRuR ^ • where R5 represents (Ci- ") alkylene group and Rn and R12 represent Η, (Ci-Ce) alkyl or form a saturated heterocyclic ring with N such as morpholinyl or hexahydropyridyl; acetyl, -COR13, its -4-f 4 (210X 297 guo) (please read the notes on the back first Please fill in this page again.) · · · · · 〇 ^ 44β Βτ C7 _; _ D7 VI. In the patent application, R13 stands for (Ci-Cd alkyl stupid; oxocarbonyl-COOR14, where Ri 4 stands for Tributyl or benzyl; and their salts. 3. The compound according to item 1 of the patent application scope, where R ζ represents Η, (Ci-Ca) alkyl or -Zi-NIUIU, which has the 1 item with the same meaning, Z stands for indolyl, which is unsubstituted or substituted on nitrogen and RIV stands for stupid group. 4. A substituted 2-amido-5- The preparation method of thiazole, in which the substituted 2-amino-5-thiazole of the following formula: (please read the note on the back and fill in this page) R〇i Where R ° α represents the same meaning as the I substituent, and the existing amine group is N-protected, RIVa and RVe represent RIV and 1 have the same meaning * wherein the hydroxyl or amine group is protected by 0- and N-, This compound is treated with a functional derivative of the formula B ° -C00H, where Z ° represents the same as the Z substituent, where the NH2 or NH group is protected, and then printed by the Central Bureau of Standards of the Ministry of Economic Affairs ^-when R ° i, when containing an N-protected or 0-protected group> deprotect this group, and the resulting product may be acylated or alkylated as appropriate to produce a compound according to item 1 of the patent application, in which the substituent R i | R ϊ v and R v are as defined in item 1 of the scope of application, or one of their salts. 5. A method for preparing a compound according to any of the formulas 1 to 3 of the patent application scope (A 4 (210X297 public issue) 6. Patent application model 6. AT B7 C7 D7 I), where Z represents The indole ring is unsubstituted on the nitrogen and optionally substituted on the stupid group, the particularity of which is the formula (I) where Z represents the corresponding compound of the indole ring, which is composed of an aminothiazole with an acid of the following formula The activated form is prepared by acylation: (Xi) ni COOH NIQ where Q represents a protecting group and Xi represents halogen * (C: t-C3) alkyl, (Ca-Cs) alkoxy, N02 mCF3, and ni is equal to ο -The three are acetylated, and the corresponding substituted indolyl group after nitrogen deprotection is produced by K. The compound of formula (XI ') X. R Υ -Ν ΝΗ- (please read the precautions on the back and then fill in the page) • Installed ... Hit · IV (XI where RIV is as defined in item 1 of the patent application scope And X represents (Ci-Cs) alkoxy I hexahydropyridyl which is unsubstituted or substituted with 4-hydroxyl or 4-alkoxycarbonyl hexahydropyridinium, wherein the alkoxy-dagger- ^ form. (IX) Compound * Line · Central Bureau of Economic Affairs of the Ministry of Economic Affairs, India X1 X2-N- (CH2) rnt 1 vs Η 2 NR IV (IX) f 4 (210X297 public) AT2〇3448 C7 D7 VI. In the patent application range ® X and CNJ or one of the 1 is Chinese E, the category of salt is defined or based on h2 N 1X I The first or the second base of the phenanthrene specialty should be applied as the table of the 8th 3, the first to the first sister of the item 1. The medicine of the first round of the mixed medicine is a kind of anti-specialty agent, and it can be used as a kind of medicine. Any of the special items (please read the notes on the back of Qiong first, and then go to this page). Installed • • Hit • • Line. Printed Armor 4 (210X297 Public Broadcasting), No. 4 Patent No. of the Party 2 ^ '^ {ti- ^ r jx Μ) Table I: Biochemical results of CCKA (rat's pancreas), CCKB (guinea pig-propagation) and gastrin (gastric gland of guinea pig) of the recipient hips 〇CCK A (Μ) • CI50 CCK B (M) CI50 gastrin (M) 1 4.10-9 7.10 · 7 2.1〇-6 2 LIO'8 LIO-5 &gt; ΙΟ'5 3 3.ΙΟ'8 1.10 -6 6.10-6 4 1.10 · 8 4.10-7 5.10-7 5 LIO · 8 &gt; 10-5 NT 6 9.10-9 &gt; 10-5 'NT 7 (1) (1) (1) 8 (1) (1) (l) 9 4.1〇-! 〇3.10-7, NT 10 3.10-9 '1.10: 7 4.10-7 _ 11 LIO'9 6.10-7, &gt; 10-5- 12 8.10-9 3.10-6 2.10-6-13 7.1〇-10 2.10-7 1.10-6 14 2.1〇-10 8.10-7 1.10-5 15 1.10-9 6_10 · 7 2.10-6 16 3.10-9 9.10-7 1.10-6 17 LIO · 9 '2.10-6 5.10-6 18 1.10-10 4.10-7 1.10-6 19 1.10 * 9 7.10-7 &gt; 10-5 20 4.1〇-10 9_10-7 1.10-6 21 2.1〇-9 1.10-6 1.10- 5 22 3.10-9 3.10-6 6.10-6 J23- 3.10-9 1.10 · 5 NT.- 24 2.10-9 2,6.1〇-6 3.10-6 25 ^ 5.10-10-9.10_5 NT _ 26 4.1〇 -10 1,7.10-6 1.10-6 27 3.10-10 1,8.10-7 7.10-7 28 1.10-9 4.10-7 • 3.IO-7 29 8.10 · 10 2_10-7 3.IO-7 30 2.10- 10 2.1〇-7 3. IO-7 31 2.10 · 10 4.1〇-7 1.10-5 32 3.10-10 6.10-7 5.IO-7 33 3.10- ^ 2.10-7 3.IO-7 34 1.10-9 6.10-7 NT 35 2.1〇- 10 9.10-8->> 3.10-L · 36 4.10 * 10 2.10-7 2.10-7 2 Office 443 Table I (continued) Instance number CI5〇CCK A (Μ) CI5〇CCK Β (Μ) α50 gastrin (Μ) ': 37 2.10'10 5.10-8 3.10-7 38 6.10-9 &gt; 10 * 5 NT 39 3.1〇-10 1.10-6 2. ΙΟ-6 40 5.1〇-10 3.10-6 2.10-6 41 3.10-10 4.10-6 3.10-6 42 2.10-9 5.10-6 7_10-6, 43 1 · 10-9 3.10-6 3.10 · 7 44 2.10'10 1.10-6 2.10-6 45 -.3.10 · 10. 5.10-7 3 · 10_7 46-5_10_10 9.10-7 · 4.10-7 47 3.10-7: &gt;10; 5 NT 48 1.10-9 3,6.10-6 &gt; 1〇-5 49 LI. · 8 &gt; ΙΟ * 5 NT 50 3.10-9 &gt; ΙΟ'5 NT 51 6.10-9 1.10-5 NT 52 3.10-9: -5.10-7 1.10-6 53 7.10-9 &gt; ΙΟ-5 NT 54 2.1 〇-8 3.10-6 NT 55 3.10-9 &gt; ΙΟ * 5 NT 56 1.10-9 &gt; ΙΟ'5 NT 57 NT NT NT 58 6.10-10 &gt; ι〇-5. NT:-. 59 a 3.10- 10 &gt; ΙΟ &quot; 5 NT 60 1 · 10-9 &gt; ΙΟ-5 NT 61 7.10-10 4. ΙΟ'7 4.10-7 62 4 · 10_7 &gt; ι〇-5 NT (1) intermediate; NT; Not tested &gt; -3-_One Table I: Inhibition of secretion of acinar amylase and inhibition of empty stomach in mice Example number Amylase secretion CI5〇 (M) (foreign) empty stomach de50 (in vivo) PO mg / kg IV mg / kg .9 1.10'8 &gt; 0.5 0.045 13 &gt; 2 0.120 14 0.66 '0.372 16 2.10-8 18 0.14 0.002' ', 20-- * &gt; 2 0.045 26-3.10-8' .. .-31 0.31; 0.350 35 0.10 '0.015-39 3.10-8 40 6.10-8 41 2.1〇-8 44 3.10-8 46 7.10-8 • 59 4.10 * 8